Use of oxindole derivatives in the treatment of dementia related diseases, alzheimer&#39;s disease and conditions associated with glycogen synthase kinase-3

ABSTRACT

The present invention relates to a new use of oxindole derivatives of formula I, as a free base or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , m and n arm as defined as in claim 1, as well as to new compounds, a process for their preparation and new intermediates used in the preparation thereof, pharmaceutical compositions containing said therapeutically active compounds and to the use of said active compounds in therapy, especially in the prevention and/or treatment of dementia related diseases, Alzheimer&#39;s Disease and conditions associated with glycogen synthase kinase-3.

FIELD OF THE INVENTION

The present invention relates to a new use of oxindole derivatives offormula I, as a free base or a pharmaceutically acceptable salt thereof,as well as to new compounds, a process for their preparation and newintermediates used in the preparation thereof, pharmaceuticalcompositions containing said therapeutically active compounds and to theuse of said active compounds in therapy, especially in the preventionand/or treatment of dementia related diseases, Alzheimer's Disease andconditions associated with glycogen synthase kinase-3.

BACKGROUND OF THE INVENTION

Glycogen synthase kinase 3 (GSK3) is a serine/threonine protein kinasecomposed of two isoformrs (α and β), which are encoded by distinct genesbut are highly homologous within the catalytic domain. GSK3 is highlyexpressed in the central and peripheral nervous system. GSK3phosphorylates several substrates including tau, β-catenin, glycogensynthase, pyruvate dehydrogenase and elongation initiation factor 2b(eIF2b). Insulin and growth factors activate protein kinase B, whichphosphorylates GSK3 on the serine 9 residue and inactivates it.

Alzheimer's Disease (AD) Dementias, and Taupathies.

AD is characterized by cognitive decline, cholinergic dysfunction andneuronal death, neurofibrillary tangles and senile plaques consisting ofamyloid-β deposits. The sequence of these events in AD is unclear, butbelieved to be related. Glycogen synthase kinase 3β (GSK3β) or Tau (τ)phosphorylating kinase selectively phosphorylates the microtubuleassociated protein τ in neurons at sites that are hyperphosphorylated inAD brains. Hyperphosphorylated protein τ has lower affinity formicrotubules and accumulates as paired helical filaments, which are themain components that constitute neurofibrillary tangles and neuropilthreads in AD brains. This results in depolymerization of microtubules,which leads to dying back of axons and neuritic dystrophy.Neurofibrillary tangles are consistently found in diseases such as AD,amyotrophic lateral sclerosis, parkinsonism-dementia complex of Gaum,corticobasal degeneration, dementia pugilistica and head trauma, Down'ssyndrome, postencephalatic parkinsonism, progressive supranuclear palsy,Niemann-Pick's Disease and Pick's Disease. Addition of amyloid-β toprimary hippocampal cultures results in hyperphosphorylation of τ and apaired helical filaments-like state via induction of GSK30 activity,followed by disruption of axonal transport and neuronal death (Imahoriand Uchida, J. Biochem 121:179-188, 1997). GSK3β preferentially labelsneurofibrillary tangles and has been shown to be active in pre-tangleneurons in AD brains. GSK3 protein levels are also increased by 50% inbrain tissue from AD patients. Furthermore, GSK30 phosphorylatespyruvate dehydrogenase, a key enzyme in the glycolytic pathway andprevents the conversion of pyruvate to acetyl-Co-A (Hoshi et al., PNAS93:2719-2723, 1996). Acetyl-Co-A is critical for the synthesis ofacetylcholine, a neurotransmitter with cognitive functions. Thus, GSK30inhibition may have beneficial effects in progression as well as thecognitive deficits associated with Alzheimer's disease and otherabove-referred to diseases.

Chronic and Acute Neurodegenerative Diseases.

Growth factor mediated activation of the PI3K/Akt pathway has been shownto play a key role in neuronal survival. The activation of this pathwayresults in GSK3β inhibition. Recent studies (Bhat et. al., PNAS97:11074-11079 (2000)) indicate that GSK3β activity is increased incellular and animal models of neurodegeneration such as cerebralischemia or after growth factor deprivation. For example, the activesite phosphorylation was increased in neurons vulnerable to apoptosis, atype of cell death commonly thought to occur in chronic and acutedegenerative diseases such as Alzheimer's Disease, Parkinson's Disease,amyotrophic lateral sclerosis, Huntington's Disease and HIV dementia,ischemic stroke and head trauma. Lithium was neuroprotective ininhibiting apoptosis in cells and in the brain at doses that resulted inthe inhibition of GSK30. Thus, GSK30 inhibitors could be useful inattenuating the course of neurodegenerative diseases.

Bipolar Disorders (BD)

Bipolar Disorders are characterised by manic episodes and depressiveepisodes. Lithium has been used to treat BD based on its moodstabilising effects. The disadvantage of lithium is the narrowtherapeutic window and the danger of overdosing, that can lead tolithium intoxication. The recent discovery that lithium inhibits GSK3 attherapeutic concentrations has raised the possibility that this enzymerepresents a key target of lithium's action in the brain (Stambolic etal., Curr. Biol. 6:1664-1668, 1996; Klein and Melton; PNAS 93:8455-8459,1996). Inhibition of GSK3β may therefore be of therapeutic relevance inthe treatment of BD as well as in AD patients that have affectivedisorders.

Schizophrenia

GSK3 is involved in signal transduction cascades of multiple cellularprocesses, particularly during neural development. Kozlovsky et al (Am JPsychiatry 2000 May;157(5):831-3) found that GSK3β levels were 41% lowerin the schizophrenic patients than in comparison subjects. This studyindicates that schizophrenia involves neurodevelopmental pathology andthat abnormal GSK3 regulation could play a role in schizophreniaFurthermore, reduced β-catenin levels have been reported in patientsexhibiting schizophrenia (Cotter et al., Neuroreport 9:1379-1383(1998)).

Diabetes

Insulin stimulates glycogen synthesis in skeletal muscles via thedephosphorylation and thus activation of glycogen synthase. Underresting conditions, GSK3 phosphorylates and inactivates glycogensynthase via dephosphorylation. GSK3 is also over-expressed in musclesfrom Type II diabetic patients (Nikoulina et al., Diabetes 2000February;49(2):263-71). Inhibition of GSK3 increases the activity ofglycogen synthase thereby decreasing glucose levels by its conversion toglycogen. GSK3 inhibition may therefore be of therapeutic relevance inthe treatment of Type I and Type II diabetes and diabetic neuropathy.

HairLoss

GSK3 phosphorylates and degrades β-catenin. β-catenin is an effector ofthe pathway for keratonin synthesis. β-catenin stabilisation may be leadto increase hair development. Mice expressing a stabilised β-catenin bymutation of sites phosphorylated by GSK3 undergo a process resembling denovo hair morphogenesis (Gat et al., Cell 1998 Nov. 25;95 (5):605-14)).The new follicles formed sebaceous glands and dermal papilla, normallyestablished only in embryogenesis. Thus GSK3 inhibition may offertreatment for baldness.

Oral Contraceptives

Vijajaraghavan et al. (Biol Reprod 2000 June; 62 (6):1647-54) reportedthat GSK3 is high in motile versus immotile sperm. Immunocytochemistryrevealed that GSK3 is present in the flagellum and the anterior portionof the sperm head. These data suggest that GSK3 could be a key elementunderlying motility initiation in the epididymis and regulation ofmature sperm function. Inhibitors of GSK3 could be useful ascontraceptives for males.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of general formula I below are disclosed in WO 97/42187.According to WO 97/42187 the effect of the compounds on reducingantiangiogenic and/or vascular permeability in mammals has beeninvestigated.

It has now surprisingly been found that the group of oxindolederivatives as decribed in WO 97/42187 are well suited for inhibitingglycogen synthase kinase-3. Said glycogen synthase kinase-3 inhibitorsare suitable in the prevention and/or treatment of conditions associatedwith glycogen synthase kinase-3 in the central and peripheral nervoussystem. In particular, the compounds of the invention are expected to besuitable for prevention and/or treatment of especially dementia relateddiseases and Alzheimer's Disease. The dementia related diseases areselected from the group consisting of Frontotemporal dementiaParkinson's Type, Parkinson dementia complex of Guam, HIV dementia,diseases with associated neurofibrillar tangle pathologies, predementedstates, vascular dementia, dementia with Lewy bodies, Frontotemporaldementia and dementia pugilistica The compounds of the invention arealso expected to be suitable for prevention and/or treatment ofamyotrophic lateral sclerosis, corticobasal degeneration, Down syndrome,Huntington's Disease, Parkinson's Disease, postencephelaticparkinsonism, progressive supranuclear palsy, Pick's Disease,Niemann-Pick's Disease, stroke, head trauma and other chronicneurodegenerative diseases, Bipolar Disease, affective disorders,depression, schizophrenia, cognitive disorders, hair loss andcontraceptive medication. The compounds of the invention are furtherexpected to be suitable for prevention and/or treatment of MildCognitive Impairment, Age-Associated Memory Impairment, Age-RelatedCognitive Decline, Cognitive Inpairment No Dementia, mild cognitivedecline, mild neurocognitive decline, Late-Life Forgetfulness, memoryimpairment and cognitive impairment and androgenetic alopecia.

In the present invention a compound of the general formula I, as a freebase or salts thereof, may be used, in the manufacturing of a medicamentfor the prevention and/or treatment of conditions associated withglycogen synthase kinase-3:

wherein:

-   R¹ is hydrogen or C₁₋₃alkyl;-   R² is hydroxy; halogeno, trifluoromethyl, cyano, amino, nitro,    carboxy, C₁₋₃alkyl,-   C₁₋₃alkoxy, C₁₋₃alkanoyloxy, C₂₋₄alkanoyl, C₁₋₄alkanoylamino,    C₁₋₄alkoxycarbonyl,-   C₁₋₄alkylthio, C₁₋₄alkylsulphinyl, C₁₋₄alkylsulphonyl, carbamoyl,    N-C₁₋₄alkylcarbamoyl,-   N,N-di(C₁₋₄alkyl)carbamoyl, aminosulphonyl,    N—C₁₋₄alkylaminosulphonyl,-   N,N-di(C₁₋₄alkyl)aminosulphonyl, C₁₋₄alkylsulphonylamino, or a group    R⁴X¹, wherein X¹ is a direct bond, C₂₋₄alkanoyl, CONR⁵R⁶, SO₂NR⁷R⁸    or SO₂R⁹ (wherein R⁵ and R⁷ each independently are hydrogen or    C₁₋₂alkyl, and R⁶, R⁸ and R⁹ each independently are C₁₋₄alkyl, and    wherein R⁴ is linked to R⁶, R⁸ or R⁹); and    -   R⁴ is phenyl or a 5 or 6 membered heterocyclic group with one or        two heteroatoms, selected independently from O, S and N, which        heterocyclic group may be saturated or unsaturated and which        phenyl or heterocyclic group may be substituted with one or two        substituents selected independently from hydoxy, halogeno,        C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkanoyloxy, trifluoromethyl, cyano,        amino, nitro and C₁₋₄alkoxycarbonyl;-   R³ is hydroxy, halogeno, nitro, trifluoromethyl, C₁₋₃alkyl, cyano,    amino or R¹⁰X², wherein X² is O, CH₂, S, SO, SO₂, NR¹¹CO, CONR¹²,    SO₂NR¹³, NR¹⁴SO₂ or NR¹⁵ (wherein R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ each    independently are hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl), or X²    is a direct bond; and    -   R¹⁰ is selected from one of the following groups:    -   1) hydrogen or C₁₋₅alkyl which may be substituted with one or        more groups selected independently from hydroxy, fluoro and        amino;    -   2) C₁₋₅alkylX³COR¹⁶(wherein X³ is O or NR¹⁷ (wherein R¹⁷ is        hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹⁸R¹⁹ is        C₁₋₃alkl, NR¹⁸R¹⁹ or OR²⁰ (wherein R¹⁸, R¹⁹ and R²⁰ each        independently are hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃allyl));    -   3) C₁₋₅alkylX⁴R²¹ (wherein X⁴ is O, S, SO, SO, SO₂, OCO, NR²²CO,        CONR²³, SO₂NR²⁴, NRSO₂ or NR² (wherein R²², R²³, R²′, R¹ and R²⁶        each independently are hydrogen, C₁₋₃alky or        C₁₋₃alkoxyC₂₋₃alkyl) and R²¹ is hydrogen, C₁₋₃alkyl,        cyclopentyl, cyclohexyl or a 5 or 6 membered saturated        heterocyclic group with one or two heteroatoms selected        independently from O, S and N, which C₁₋₃alkyl group may be        substituted with one or two substituents selected independently        from oxo, hydroxy, halogeno and C₁₋₄alkoxy and which        heterocyclic group may be substituted with one or two        substituents selected independently from oxo, hydroxy, halogeno,        C₁₋₄alkyl, C₁₋₄hydroxyalkyl and C₁₋₄alkoxy);-   4) C₁₋₅alkylX⁵C₁₋₅alkylX⁶R²⁷ (wherein X⁵ and X⁶ each independently    are O, S, SO, SO₂, NR²⁸CO, CONR²⁹, SO₂NR³⁰, NR³¹SO₂ or NR³² (wherein    R²⁸, R²⁹, R³⁰, R³¹ and R³² each independently are hydrogen,    C₁₋₃alkyl or C₁₋₃alkoXYC₂₋₃alkyl) and R²⁷ is hydrogen or C₁₋₃alkyl);    -   5) C₁₋₅alkylR³³(wherein R³³ is a 5 or 6 membered saturated        heterocyclic group with one or two heteroatoms selected        independently from O, S and N, which heterocyclic group may be        substituted with one or two substituents selected independently        from oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₆carbonyl,        C₁₋₄hydroxyalkyl and C₁₋₄alkoxy);    -   6) C₂₋₅alkenylR³³ (wherein R³³ is as defined hereinbefore);    -   7) C₂₋₅alkynylR³³ (wherein R³³ is as defined hereinbefore);    -   8) R³⁴ (wherein R³⁴ is a pyridone group, a phenyl group or a 5        or 6 membered aromatic heterocyclic group with 1 to 3        heteroatoms selected independently from O, N and S, which        pyridone, phenyl or heterocyclic group may carry up to 5        substituents selected independently from hydroxy, halogeno,        amino, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl,        C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy cyano CONR³⁵R³⁶ and        NR³⁷COR³⁸ (wherein R³⁵, R³⁶, R³⁷ and R³⁸ each independently are        hydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl));    -   9) C₁₋₅alkylR³⁴ (wherein R³⁴ is as defined hereinbefore);    -   10) C₂₋₅alkenylR³⁴ (wherein R³⁴ is as defined hereinbefore);    -   11) C₂₋₅alkynylR³⁴ (wherein R³⁴ is as defined hereinbefore);    -   12) C₁₋₅alkylX⁷R³⁴ (wherein X⁷ is O, S, SO, SO₂, NR³⁹CO, CONR⁴⁰,        SO₂NR⁴¹, NR⁴²SO₂ or NO (wherein R³⁹, R⁴⁰, R⁴¹, R⁴² and R⁴³ each        independently are hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)        and R³⁴ is as defined hereinbefore);    -   13) C₂₋₅alkenylX⁸R³⁴ (wherein X⁸ is O, S, SO, SO₂, NR⁴⁴CO,        CONR⁴⁵, SO₂NR⁴⁶, NR⁴⁷SO₂ or NR⁴⁸ (wherein R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷ and        R⁴⁸ each independently are hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R³⁴ is as defined hereinbefore);    -   14) C₂₋₅alkynylX⁹R³⁴ (wherein X⁹ is O, S, SO, SO₂, NR⁴⁹CO,        CONR⁵⁰, SO₂NR⁵¹, NR⁵²SO₂ or N (wherein R⁴⁹, R⁵⁰, R⁵¹, R⁵² and        R⁵³ each independently are hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R³⁴ is as defined hereinbefore);    -   15) C₁₋₃alkylX¹⁰C₁₋₃alkylR³⁴ (wherein X¹⁰ is O, S, SO, SO₂,        NR⁵⁴CO, ONR⁵⁵, SO₂NR⁵⁶, NR¹⁷SO₂ or NR⁵⁸ (wherein R⁴, R⁵⁵, R⁵⁶,        R⁵⁷ and R⁵⁸ each independently are hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R³⁴ is as defined hereinbefore);    -   16) R³³ (wherein R³³ is as defined hereinbefore); and    -   17) C₁₋₃alkylX¹⁰C₁₋₃alkylR³³ (wherein X¹⁰ and R³³ are as defined        hereinbefore);    -   18) C₁₋₅alkylCOR³³ (wherein R³³ is as defined hereinbefore);-   n is 0, 1, 2, 3 or 4;-   m is 0, 1, 2, 3 or 4;    as a free base or a pharmaceutically acceptable salt thereof.

One aspect of the invention relates to the use of compounds of formulaI, wherein R³ is R¹⁰X²,

wherein X² is O, CH₂, S, SO, SO₂, NR¹¹CO, CONR¹², SO₂NR¹³, NR¹⁴SO₂ orNR¹⁵ (wherein R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ each independently arehydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl), or X² is a direct bond; and

-   R¹⁰ is selected from one of the following groups:    -   1) hydrogen or C₁₋₅alkyl which may be substituted with one or        more groups selected independently from hydroxy, fluoro and        amino;    -   2) C₁₋₅alkylX³COR¹⁶ (wherein X³ is O or NR¹⁷ (wherein R¹⁷ is        hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹⁶ is        C₁₋₃alkyl, NR¹⁸R¹⁹ or OR²⁰ (wherein R¹⁸, R¹⁹ and R² each        independently are hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl));    -   3) C₁₋₅alkylX⁴R²¹ (wherein X⁴ is O, S, SO, SO₂, OCO, NR²²CO,        CONR²³, SO₂NR²⁴, NR²⁵SO₂ or NR²⁶ (wherein R²², R²³, R²⁴, R²⁵ and        R²⁶ each independently are hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R²¹ is hydrogen, C₁₋₃alkyl,        cyclopentyl, cyclohexyl or a 5 or 6 membered saturated        heterocyclic group with one or two heteroatoms selected        independently from O, S and N, which C₁₋₃alkyl group may be        substituted with one or two substituents selected independently        from oxo, hydroxy, halogeno and C₁₋₄alkoxy and which        heterocyclic group may be substituted with one or two        substituents selected independently from oxo, hydroxy, halogeno,        C₁₋₄alkyl, C₁₋₄hydroxyalkyl and C₁₋₄alkoxy);    -   4) C₁₋₅alkylX⁵C₁₋₅alkylX⁶R²⁷ (wherein X⁵ and X⁶ each        independently are O, S, SO, SO₂, NR²⁸CO, CONR²⁹, SO₂NR³⁰,        NR³¹SO₂ or NR³² (wherein R²⁸, R²⁹, R³⁰, R³¹ and R³² each        independently are hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)        and R²⁷ is hydrogen or C₁₋₃alkyl);    -   5) C₁₋₅alkylR³³ (wherein R³³ is a 5 or 6 membered saturated        heterocyclic group with one or two heteroatorns selected        independently from O, S and N, which heterocyclic group may be        substituted with one or two substituents selected independently        from oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl and        C₁₋₄alkoxy);    -   6) C₂₋₅alkenylR³³ (wherein R³³ is as defined hereinbefore);    -   7) C₂₋₅alkenylR³³ (wherein R³³ is as defined hereinbefore);    -   8) R³⁴ (wherein R³⁴ is a pyridone group, a phenyl group or a 5        or 6 membered aromatic heterocyclic group with 1 to 3        heteroatoms selected independently from O, N and S, which        pyridone, phenyl or heterocyclic group may carry up to 5        substituents selected independently from hydroxy, halogeno,        amino, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl,        C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy, cyano, CONR³⁵R³⁶ and        NR³⁷COR³⁸ (wherein R³⁵, R³⁶, R³⁷ and R³⁸ each independently are        hydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl));    -   9) C₁₋₅alkylR³⁴ (wherein R³⁴ is as defined hereinbefore);    -   10) C₂₋₅alkenyR³⁴ (wherein R³⁴ is as defined hereinbefore);    -   11) C₂₋₅alkenylR³⁴ (wherein R³⁴ is as defined hereinbefore);    -   12) C₁₋₅alkylX⁷R³⁴ (wherein X⁷ is O. S. SO, SO₂, NR³⁹CO, CONR⁴⁰,        SO₂NR⁴⁶ NR⁴²SO₂ or NR⁴³ (wherein R³⁹, R⁴⁰, R⁴¹R⁴² and R⁴³ each        independently are hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)        and R³⁴ is as defined hereinbefore);    -   13) C₂₋₅alkyl (where X⁸ is O, S, SO, SO₂, NR⁴⁴CO, CONR⁴⁵,        SO₂NR⁴⁶, NR⁴⁷SO₂ or NR⁴⁸ (wherein R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸ each        independently are hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)        and R³⁴ is as defined hereinbefore);    -   14) C₂₋₅alkynylX⁹R³⁴ (wherein X⁹ is O, S, SO, SO₂, NR⁴⁹CO,        CONR⁵⁰, SO₂NR⁵¹′, NR⁵²SO₂ or NR⁵³ (wherein R⁴⁹, R⁵⁰, R⁵¹, R⁵²        and R⁵³ each independently are hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R³⁴ is as defined hereinbefore);    -   15) C₂₋₃alkylX¹⁰C₁₋₃alkylR³⁴(wherein X¹⁰ is O, S, SO, SO₂,        NR⁵⁴CO, ONR⁵⁵, SO₂NR⁵⁶, NR⁵⁷ SO₂ or NR⁵⁸ (wherein R⁵⁴, R⁵⁵, R⁵⁶,        R⁵⁷ and R⁵⁸ each independently are hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R³⁴ is as defined hereinbefore);    -   16) R³³ (wherein R³³ is as defined hereinbefore); and-   17) C₁₋₃alkylX¹⁰C₁₋₃alkylR³³ (wherein X¹⁰ and R³³ are as defined    hereinbefore).

Another aspect of the invention relates to the use of compounds offormula I, wherein R¹ is hydrogen.

In a further aspect of the invention compounds of formula I may be used,wherein R² is halogeno, cyano, nitro, carboxy, C₁₋₄alkoxycarbonyl,trifluoromethyl, C₁₋₃alkyl, C₁₋₃alkoxy, N-C₁₋₄alkylcarbamoyl,N,N-di(C₁₋₄alkyl)carbamoyl, aminosulphonyl, or a group R⁴X¹,

-   -   wherein X¹ is CONR⁵R⁶, (wherein R⁵ is hydrogen or C₁₋₂alkyl, and        R⁶ is C₁₋₄alkyl, and wherein R⁴ is linked to R⁶; and    -   R⁴ is phenyl or a 5 or 6 membered heterocyclic group with one or        two heteroatoms, selected independently from O and N, which        heterocyclic group may be saturated or unsaturated and which        phenyl or heterocyclic group may be substituted with one or two        substituents selected independently from hydroxy, halogeno,        C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkanoyloxy, trifluoromethyl, cyano,        amino, nitro and C₁₋₄alkoxycarbonyl;

-   n is 0, 1 or 2.

In one aspect of the invention compounds of formula I may be used,

-   wherein R³ is R¹⁰X²,    -   wherein xX² is O; and    -   R¹⁰ is selected from one of the following groups:    -   1) hydrogen or C₁₋₅alkyl;    -   3) C₁₋₅alkylX⁴R²¹ (wherein X⁴ is O or NR²⁶ (wherein R²¹ and R²⁶        each independently are hydrogen, C₁₋₃alkyl, cyclopentyl or        cyclohexyl));    -   4) C₁₋₅alkylX⁵C₁₋₅alkylX⁶R²⁷ (wherein X⁵ and X⁶ are O and R²⁷ is        hydrogen or C₁₋₃alkyl);    -   5) C₁₋₅alkylR³³ (wherein R³³ is a 5 or 6 membered saturated        heterocyclic group with one or two heteroatoms, selected        independently from O, S and N, which heterocyclic group may be        substituted with one or two substituents selected independently        from oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁carbonyl,        C₁₋₄hydroxyalkyl and C₁ alkoxy);    -   9) C₁₋₅alkylR³⁴ (wherein R³⁴ is a 5 membered aromatic        heterocyclic group with 1 to 3 heteroatoms selected        independently from O and N, which heterocyclic group may carry        up to 5 substituents selected independently from halogeno,        amino, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalyl, C₁₋₄aminoalkyl,        C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy, hydoxy, cyano,        CONR³⁵R³⁶ and NR³⁷COR³⁸(wherein R³⁵, R³⁶, R³⁷ and R³⁸ each        independently are hydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl));        and    -   17) C₁₋₃alkylX¹⁰C₁₋₃alkylR³³ (wherein X¹⁰ is O and R³³ are as        defined hereinbefore);    -   18) C_, alkylCOR³³ (wherein R³³ is as defined hereinbefore); m        is 0, 1 or 2.

In another aspect of the invention compounds of formula I may be used,

-   wherein R³ is R¹⁰X²,-   wherein X² is O; and R¹⁰ is    -   4) C₁₋₅alkylX⁵C₁₋₅alkylX⁶R²⁷ (wherein X⁵ and X⁶ are O and R²⁷ is        hydrogen or C₁₋₃alkyl).

In yet another aspect of the invention compounds of formula I may beused, wherein the R² is substituted on position 5 and/or 6 and R³ issubstituted on position 6, 7 and/or 8.

The present invention further relates to novel compounds, which are

-   4-(6-Fluorooxindol-3-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,-   4-(5-Cyanooxindol-3-yl)-6-methoxy-7-(2-methoxyethoxy)quinazoline,-   4-(5-Cyanooxindol-3-yl)-7-(2-methoxyethoxy)quinazoline,-   4-(5-Cyanooxindol-3-yl)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline,-   4-(5-Cyanooxindol-3-yl)-7-(3-morpholinopropoxy)quinazoline,-   4-(5-Carbanoyloxindol-3-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,-   4-(6-Cyanooxindol-3-yl)methoxy-7-(3-morpholinopropoxy)quinazoline,-   4-(6-Bromooxindol-3-yl)-7-(3-morpholinopropoxy)quinazoline,-   2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic    acid (4-phenylbutyl)amide,-   6-Chloro-3-[7-(3-morpholin-4-yl-propoxy)quinazolin-4-yl]-1,3-dihydro-indol-2-one-   hydrochloride,-   3-{7-[2-(2-Methoxyethoxy)ethoxy]quinazolin-4-yl}-1,3-dihydroindol-2-one    hydrochloride,-   6-Fluoro-3-[7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]-1,3-dihydro-indol-2-one    dihydrochloride,-   7-Fluoro-3-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]-1,3-dihydroindol-2-one    dihydrochloride,-   3-[7-(3-Morpholin-4-ylpropoxy)quinazolin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carboxylic    acid dimethylamide,-   3-[7-(3-Morpholinylpropoxy)quinazolin-4-yl]-6-propyl-1H-indol-2-ol    hydrochloride,-   6-Ethyl-3-[7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]-1H-indol-2-ol    hydrochloride,-   2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic    acid [2-(1-methylpyrrolidin-2-yl)ethyl]amide,-   2-Hydroxy-3-[7-(2-morpholin-4-ylethoxy)quinazolin-4-yl]-1H-indole-5-carbonitril    dihydrochloride,-   2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic    acid (tetrahydrofuran-2-ylmethyl)amide,-   2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic    acid (3-morpholin-4-ylpropyl)amide,-   2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic    acid [2-(1H-imidazol-4yl)ethyl)amide,-   2-Hydroxy-3-{7-[2-(2-methoxyethoxy)ethoxy]quinazolin-4-yl}-1H-indole-5-carbonitrile    hydrochloride,-   3-[7-(2-Imidazol-1-yl-ethoxy)-6-methoxyquinazolin-4-yl]-2-oxo-2,3-dihydro-H-indole-5-sulfonamide    acetate,-   6-Bromo-3-[6-methoxy-7-(3-morpholin-4-yl-propoxy)quinazolin-4-yl]-1,3-dihydroindol-2-one    dihydrochloride,-   6-Bromo-3-quinazolin-4-yl-1,3-dihydroindol-2-one,-   6-Bromo-3-{6-methoxy-7-[2-(2-methoxyethoxy)ethoxy]quinazolin-4-yl}-1,3-dihydroindol-2-one    hydrochloride,-   3-{7-[2-(2-Morpholin-4-yl-ethoxy)ethoxy]quinazolin-4-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile    hydrochloride,-   6-Chloro-3-{7-[2-(2-methoxyethoxy)ethoxy]quinazolin-4-yl}-1,3-dihydroindol-2-one    hydrochloride,-   3-{7-[2-(4-Acetylpiperazin-1-yl)ethoxy]quinazolin-4-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile    hydrochloride,-   5-Chloro-3-{7-[2-(2-methoxyethoxy)ethoxy]quinazolin-4-yl}-1,3-dihydroindol-2-one    hydrochloride,-   3-{7-[2-(4-Butyrylpiperazin-1-yl)ethoxy]quinazolin-4-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile    hydrochloride,-   3-{7-[2-(4-Acetylpiperazin-1-yl)-2-oxoethoxy]quinazolin-4-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile    hydrochloride,-   3-{7-[4-(4-Acetylpiperazin-1-yl}-4-oxobutoxy]quinazolin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile    hydrochloride,-   6-Bromo-3-[7-(2-imidazol-1-ylethoxy)-6-methoxyquinazolin-4-yl]-1,3-dihydro-indol-2-one    dihydrochloride,-   3-[7-(2-Imidazol-1-ylethoxy)-6-methoxyquinazolin-4-yl]-2-oxo-2,3-dihydro-1H-indole-6-carbonitrile    dihydrochloride,-   3-[7-(3-Morpholinylpropoxy]quinazolintyl]-2-oxo-2,3-dihydro-1H-indole-5-carboxylic    acid methylamide,-   3-{7-[3-(4-Methylpiperazin-1-yl)propoxy]quinazolin-4-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile    hydrochloride,-   2-Hydroxy-3-[8-(2-morpholin-4-ylethoxy)quinazolin-4-yl]-1H-indole-5-carbonitrile    hydrochloride,-   6-Bromo-3-[7-(3-morpholin-4-ylpropoxy)quiazolin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carboxylic    acid methylamide,-   6-Methyl-3-[7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]-1H-indol-2-ol,-   5-Bromo-6-methyl-3-[7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]-1H-indol-2-ol    dihydrochloride,-   6-Bromo-3-[7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]-5-nitro-1H-indol-2-ol    dihydrochloride,-   2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic    acid,-   3-[7-(3-Dimethylaminopropoxy)quinazolin-4-yl]-2-hydoxy-1H-indol-5-carbonitrile    hydrochloride,-   3-[7-(2-Dimethylaminoethoxy)quinazolin-4-yl]-2-hydoxy-1H-indol-5-carbonitrile    fumarate,-   3-{7-[2-(Isopropylmethylamino)ethoxy]quinazolin-4-yl}-2-oxo-2,3-dihydro-1H-indol-5-carbonitrile    fumarate and-   3-[7-(2-Diisopropylamino)ethoxy)quinazolin-4-yl]-2-hydroxy-1H-indol-5-carbonitrile    fumarate,    as a free base or salts thereof.

In another aspect of the invention the compounds listed hereinbefore maybe used in the manufacturing of a medicament for the prevention and/ortreatment of conditions associated with glycogen synthase kinase-3.

For the avoidance of doubt it is to be understood that where in thisspecification a group is qualified by ‘hereinbefore defined’ or ‘definedhereinbefore’ the said group encompasses the first occurring andbroadest definition as well as each and all of the preferred definitionsof that group.

For the avoidance of doubt it is to be understood that in thisspecification ‘C₁₋₅’ means a carbon group having 1, 2, 3, 4 or 5 carbonatoms.

In this specification, unless stated otherwise, the term “alkyl”includes both straight and branched chain alkyl groups. C₁₋₅alkyl may bemethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl,n-pentyl, i-pentyl, t-pentyl, neo-pentyl.

The term “alkoxy” as used herein, unless stated otherwise includes“alkyl”O groups in which “alkyl” is as hereinbefore defined. C₁₋₅alkoxymay be methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy,s-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, t-pentyloxy,neo-pentyloxy.

The term “alkanoyl” as used herein, unless otherwise stated includesformyl and alkylC═O groups in which “alkyl” is as defined hereinbefore,for example C₂alkanoyl is ethanoyl and refers to CH₃C═O, C₁alkanoyl isformyl and refers to CHO.

In this specification, unless stated otherwise, the term “alkenyl”includes both straight and branched chain alkenyl groups but referencesto individual alkenyl groups such as 2-butenyl are specific for thestraight chain version only. Unless otherwise stated, the term “alkenyl”advantageously refers to chains with 2 to 5 carbon atoms, preferably 3to 4 carbon atoms.

In this specification, unless stated otherwise, the term “alkynyl”includes both straight and branched chain alkynyl groups but referencesto individual alkynyl groups such as 2-butynyl are specific for thestraight chain version only. Unless otherwise stated, the term “alkynyl”advantageously refers to chains with 2 to 5 carbon atoms, preferably 3to 4 carbon atoms.

In this specification, unless stated otherwise, the term “5 or 6membered heterocyclic group with one or two heteroatoms, selectedindependently from O, S and N, which heterocyclic group may be saturatedor unsaturated” includes both heteroaromatic rings and heterocyclicrings that are saturated. Examples of such heterocyclic groups includes,but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl,oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl,pyrrolyl, thiazolyl, thienyl, imidazolidinyl, imidazolinyl, morpholinyl,piperazinyl, piperidyl, piperidonyl, pyrazolidinyl, pyrazolinyl,pyrrolidinyl, pyrrolinyl, tetrahydropyranyl or thiomorpholinyl.

In this specification, unless stated otherwise, the term “5 or 6membered saturated heterocyclic group with one or two heteroatoms,selected independently from O, S and N” may be, but are not limited to,pyrrolidinyl, imidazoiudinyl, pyrazolidinyl, morpholinyl, piperidinyl,oxathianyl, thiomorpholinyl, piperazinyl. In this specification, unlessstated otherwise, the term “5 or 6 membered aromatic heterocyclic groupwith 1 to 3 heteroatoms, selected independently from O, N and S” may be,but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl,oxazolyl, pyrazinyl, triazinyl, pyrazolyl, pyridazinyl, pyridyl,pyrimidyl, pyrrolyl, thiazolyl or thienyl.

In this specification, unless stated otherwise, the term halogeno may befluor, chlorine, bromine or iodine. For the avoidance of any doubt, itis to be understood that when X² is, for example, a group of formulaNR¹¹CO, it is the nitrogen atom be substituted withing the R¹¹ groupwhich is attached to the quinazoline ring and the carbonyl (CO) group isattached to R¹⁰, whereas when X² is, for example, a group of formulaCONR¹², it is the carbonyl group which is attached to the quinazolinering and the nitrogen atom be substituted withing the R¹² group isattached to R¹⁰. A similar convention applies to the other two atoms X²linking groups such as NR¹⁴SO₂ and SO₂NR¹³. When X² is NR¹⁵ it is thenitrogen atom be substituted withing the R¹⁵ group which is linked tothe quinazoline ring and to R¹⁰. An analogous convention applies toother groups. It is further to be understood that when x² is NR¹⁵ andR¹⁵ is C₁₋₃alkoxyC₂₋₃alkyl it is the C₂₋₃alkyl moiety, which is linkedto the nitrogen atom of X² and an analogous convention applies to othergroups.

For the avoidance of any doubt, it is to be understood that in acompound of the formula I when R¹⁰ is, for example, a group of formulaC₁₋₅alkylX¹⁰C₁₋₅alkylR³⁴, it is the terminal C₁₋₅alkyl moiety, which islinked to X², similarly when R¹⁰ is, for example, a group of formulaC₂₋₅alkenylR³⁴ it is the C₂₋₅alkenyl moiety which is linked to X² and ananalogous convention applies to other groups.

For the avoidance of any doubt, it is to be understood that when R³⁴carries a C₁₋₄aminoalkyl substituent it is the C₁₋₄alkyl moiety which isattached to R³ whereas when R³⁴ carries a C₁₋₄alkylamino substituent itis the amino moiety which is attached to R³⁴ and an analogous conventionapplies to other groups.

For the avoidance of any doubt when X¹ is C₂₋₄alkanoyl it is thecarbonyl moiety which is linked to the benzen ring of the oxindole groupand it is the alkyl moiety which is linked to R⁴ and an analogousconvention applies to other groups.

Some compounds of formula I may have chiral centres and/or geometricisomeric centres (E- and D isomers), and it is to be understood that theinvention encompasses all such optical, diastereoisomers and geometricisomers that possess GSK3 inhibitory activity.

It is to be understood that the present invention also relates to anyand all tautomeric forms of the compounds of formula I.

The present invention relates to the use of compounds of formula I andto new compounds as hereinbefore defined as well as to the saltsthereof. Salts for use in pharmaceutical compositions will bepharmaceutically acceptable salts, but other salts may be useful in theproduction of the compounds of formula I and their pharmaceuticallyacceptable salts. Both organic and inorganic acids can be employed toform non-toxic pharmaceutically acceptable acid addition salts of thecompounds of this invention. In addition, a suitable pharmaceuticallyacceptable salt of the compounds of the invention is an alkali metalsalt, an alkaline earth metal salt or a salt with an organic base.

The present invention further relates to intermediates used for thepreparation of compounds of formula I.

The intermediates are

-   2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic    acid,-   Methyl    2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylate,-   7-(2-Morpholin-4-yl)ethoxy)-3H-quinazolin-4-one,-   4-Chloro-7-[(2-morpholinyl)ethoxy]quinazoline,-   7-[2-(2-Methoxyethoxy)ethoxy]-3H-quinazolin-4-one,-   4-Chloro-7-[2-(2-methoxyethoxy)ethoxy]quinazoline,-   4-(Methylthio)-7-[2-(2-morpholin-4-ylethoxy)ethoxy]quinazoline,-   7-[2-(4-Acetylpiperazin-1-yl)ethoxy]4-methylthioquinazoline,-   7-(2-Bromoethoxy)-4-(methylthio)quinazoline,-   7-[2-(4-Butyrylpiperazin-1-yl)ethoxy]4-(methylthio)quinazoline,-   7-[2-(4-Acetylpiperazin-1-yl)-2-oxoethoxy]-4(methylthio)quinazoline,-   1-Acetyl-4-(4-chlorobutanoyl)piperazine,-   7-[4-(4-Acetylpiperazin-1-yl)₄-oxobutoxy]-4-(methylthio)quinazoline,-   2-Oxo-2,3-dihydro-1H-indole-5-carboxylic acid dimethylamide,-   2-Oxo-2,3-dihydro-1H-indole-5-carboxylic acid methylamide,-   7-[3-(4-Methylpiperazin-1-yl)propoxy]-3H-quinazolin-4-one,-   4-Chloro-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline,-   4-Chloro-8-(2-morpholin-4-ylethoxy)quinazoline,-   6-Bromo-5-(2-chloroacetyl) 1,3-dihydroindol-2-one,-   6-Bromo-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid,-   6-Bromo-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methylamide,-   2-(4-Ethylphenyl)-N-methoxyacetamide,-   6-Ethyl-1-methoxy-1,3-dihydroindol-2-one,-   6-Ethyl-1,3-dihydroindol-2-one,-   N-Methoxy-2-(4-propylphenyl)acetamide,-   1-Methoxy-6-propyl-1,3-dihydroindol-2-one,-   6-Propyl-1,3-dihydroindol-2-one,-   5-Bromo-6-methyl-1,3-dihydroindol-2-one,-   6-Bromo-5-nitro-1,3-dihydroindol-2-one,-   7-(3-Dimethylaminopropoxy)-3H-quinazolin-4-one,-   7-(2-Dimethylaminoethoxy)-3H-quinazolin-4-one,-   7-[2-(Isopropylmethylamino)ethoxy]-3H-quinazolin-4-one,-   7-(2-Diisopropylaminoethoxy)-3H-quinazolin-4-one,-   [3-(4-Chloroquinazolin-7-yloxy)propyldimethylamine,-   [2-(4-Chloroquinazolin-7-yloxy)ethyl]dimethylamine,-   [2-(4-Chloroquinazolin-7-yloxy)ethyl]isopropylmethylamine and-   [2-(4-Chloro-quinazolin-7-yloxy)ethyl]diisopropylamine.    Methods of Preparation

Compounds of formula I, or salt thereof, may be prepared by any processknown to be applicable to the preparation of chemically-relatedcompounds. Such processes include, for example, those illustrated inEuropean Patent Applications Publication Nos. 0520722, 0566226, 0602851,0635498 and 0636608 and PCT application WO 97/42187.

The present invention also relates to processes for preparing thecompounds of formula I. Throughout the following description of suchprocesses it is understood that, where appropriate, suitable protectinggroups will be added to, and subsequently removed from, the variousreactants and intermediates in a manner that will be readily understoodby one skilled in the art of organic synthesis. Conventional proceduresfor using such protecting groups as well as examples of suitableprotecting groups are described, for example, in “Protective Groups inOrganic Synthesis” T. W. Greene, P. G. M. Wuts, Wiley-Interscience, NewYork, 1999.

The terms “room” and “ambient” temperature refer to a temperaturebetween 16° C. and 25° C.Methods of Preparation of Intermediates

(i) Conversion of a compound of formula II to a compound of formula III,wherein R¹⁰ is as defined in formula I, may be carried with a suitablereagent R¹⁰—OH in a suitable solvent such as dimethylsulphoxide, dioxaneor N,N-dimethylformamide in the presence of a suitable base such as analkali metal or alkaline earth metal carbonate or hydroxide such assodium carbonate, potassium carbonate, calcium carbonate, sodiumhydroxide or potassium hydroxide or an alkali metal hydride such assodium hydride, or an alkali metal or alkaline earth metal amide such assodium amide, sodium bis(trinethylsilyl)amide, potassium amide orpotassium bis(trimethylsilyl)amide and the reaction may occur at atemperature between 0° C. and +150° C.

(ii) Conversion of a compound of formula III to a compound of formulaIV, wherein L¹ is a suitable leaving group such as a halogeno e.g.chlorine or bromine, may be carried with a suitable halogenation reagentsuch as thionyl chloride, oxalyl chloride, phosphorus oxychloride,phosphoric trichloride or aluminum tribromide in a suitable solvent suchas methylene chloride, chloroform, toluene or using the halogenationreagent neat and the reaction may occur at a temperature between +20° C.and +130° C.

(iii) Conversion of a compound of formula V to a compound of formula VI,wherein R^(10a) is C₂-C₅alkyl-L², wherein L² is a suitable leaving groupsuch as a halogeno e.g. chlorine or bromine, or R^(10a) is R¹⁰ whereinR¹⁰ is as defined in formula I, may be carried out with a suitablereagent such asa) an alkylating reagent of the formula IX or a reagentL²—C₂-C₅alkyl-L³, wherein L² and L³ may be the same or different, e.g.halogeno e.g. chlorine or bromine, in a suitable solvent such asN,N-dimethylformamide, methylene chloride or acetonitrile in thepresence of a suitable base such as an alkali metal or alkaline earthmetal carbonate or hydroxide such as sodium carbonate, potassiumcarbonate, calcium carbonate, sodium hydroxide or potassium hydroxide oran alkyl amine base such as triethyl amine and the reaction may occurbetween +20° C. and +150° C., orb) R¹⁰—OH in a suitable solvent such as methylene chloride, chloroform,diethyl ether or tetrahydrofuran in the presence of a suitable couplingreagent such as diisopropyl azocarbodiimide or diethyl azocarbodiimideand triphenylphosphine and the reaction may occur at a temperaturebetween +10 and +150° C.

(iv) Conversion of a compound of formula VI, wherein R^(10a) isC₂-C₅alkyl-L², wherein L² is a suitable leaving group such as a halogenoe.g. chlorine or bromine, to a compound of formula VII, wherein R¹⁰ isas defined in formula I, may be carried out by

alkylation of a compound of formula VIII, wherein R is an alkanoylgroup, in a suitable solvent such as N,N-dimethylformamide, methylenechloride or acetonitrile or using a compound of formula VIII neat andthe reaction may occur at a temperature between +20 and +150° C.

(v) Conversion of a compound of formula VIII, wherein R is an alkanoylgroup, to a compound of formula IX, wherein R^(a) is C₁-C₅alkylL³ and L³is as defined above may be carried out by reaction with a reagentL²(CO)C₁-C₅alkylL³, wherein L² and L³ may be the same or different andare defined as above, in a suitable solvent such as methylene chloride,chloroform or acetonitrile in the presence of a suitable base such as analkali metal or alkaline earth metal carbonate or hydroxide such assodium carbonate, potassium carbonate, calcium carbonate, sodiumhydroxide or potassium hydroxide or an alkyl amine base such as triethylamine and the reaction may occur at a temperature between −70° C. and+80° C.

(vi) Conversion of a compound of formula X to a compound of formula XI,wherein R¹⁰ is as defined in formula I, may be carried out with asuitable reagent such as R¹⁰—OH in as suitable solvent such as methylenechloride, chloroform, diethyl ether or tetrahydrofuran in the presenceof a suitable coupling reagent such as diisopropyl azocarbodiimide ordiethyl azocarbodjimide and triphenylphosphine and the reaction mayoccur at a temperature between +10 and +150° C.

(vii) Conversion of a compound of formula XII to a compound of formulaXIII, wherein R^(C) and R^(D) is hydrogen or C₁₋₄alkyl, may be carriedout by activation of the acid function in a compound of formula XII

-   a) with a halogenation reagent such as thionyl chloride or oxalyl    chlorid in a suitable solvent such as methylene chloride or toluene    or using the reagent neat folllowed by a reaction with the    appropriate substituted amine R^(C)R^(D)NH in a suitable solvent    such as methylene chloride, chloroform or acetonitrile in the    presence of a suitable base such as an alkali metal or alkaline    earth metal carbonate or hydroxide such as sodium carbonate,    potassium carbonate, calcium carbonate, sodium hydroxide or    potassium hydroxide or an alkyl amine base such as triethyl amine    and the reaction may occur at a temperature between −70° C. and +80°    C., or    b) with a suitable coupling reagent such as 1,1′-carbonyldiimidazole    or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide in a suitable    solvent such as N,N-dimethylformamide or tetrahydrofuran followed by    addition and reaction with the appropriate substituted amine    R^(C)R^(D)NH and at a reaction temperature between +20° C. and +130°    C.    (viii) Conversion of a compound of formula XIV to a compound of    formula XV, wherein halo is halogeno and is as defined in formula I,    may be carried out by-   a) a Friedel-Craft acylation using acylating reagent such as    chloroacetyl chloride and aluminum trichloride in a suitable solvent    such as methylene chloride, chloroform or nitrobenzene and at a    reaction temperature between +o ° C. and 60° C., followed by,-   b) reaction of the formed chloroketone with pyridine followed by    hydrolysis in a suitable solvent such as water or a mixture of water    and an alcohol such as ethanol or methanol in the presence of a    suitable base such as sodium hydroxide or potassium hydroxide and at    a reaction temperature between +20° C. and reflux resulting in a    compound of formula XV.    (ix) Conversion of a compound of formula XV to a compound of formula    XVI, wherein R^(C) and R^(D) are as defined hereinbefore,    may be carried out by activation of the acid function in a compound    of formula XV,-   a) with a halogenation reagent such as thionyl chloride or oxalyl    chlorid in a suitable solvent such as methylene chloride or toluene    or using the reagent neat followed by reaction with the appropriate    substituted amine R^(C)R^(D)NH in a suitable solvent such as    methylene chloride, chloroform or acetonitrile in the presence of a    suitable base such as an alkali metal or alkaline earth metal    carbonate or hydroxide such as sodium carbonate, potassium    carbonate, calcium carbonate, sodium hydroxide or potassium    hydroxide or an alkyl amine base such as triethyl amine and the    reaction may occur at a temperature between −70° C. and +80° C., or-   b) with a suitable coupling reagent such as 1,1′-carbonyldiimidazole    or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide in a suitable    solvent such as N,N-dimethylformarmide or tetrahydrofuran followed    by addition and reaction with the appropriate substituted amine    RCRDNH and at a reaction temperature between +20° C. and +130° C.    (x) Conversion of a compound of formula XVII to a compound of    formula XVIII, wherein R² is C₁₋₃alkyl, may be carried out by-   a) activation of the acid function in a compound of formula XVII    with a halogenation reagent such as thionyl chloride or oxalyl    chlorid in a suitable solvent such as methylene chloride or toluene    or using the reagent neat and at a reaction temperature between    +20° C. and reflux, followed by,-   b) conversion of the acid chloride to the corresponding    N-methoxycarboxamide by a reaction with methoxyamine hydrochloride    in an appropriate solvent such as methylene chloride, chloroform or    toluene or solvent mixtures with water such as toluene and water in    the presence of a suitable base such as an alkali metal or alkaline    earth metal carbonate or hydroxide such as sodium carbonate,    potassium carbonate, calcium carbonate, sodium hydroxide or    potassium hydroxide or an alkyl amine base such as triethyl amine    and the reaction may occur between +20° C. and +120° C., followed    by,-   c) cyclization, to form the compound of formula XVIU, wherein R² is    C₁₋₃alkyl, in a suitable solvent such as methylene chloride or    chloroform using a suitable reagent such as tert-butyl hypochlorite    and at a reaction temperature between ±0° C. and reflux.-   (xi) Conversion of a compound of formula XVIII to a compound of    formula XIX, wherein R² is C₁₋₃alkyl, may be carried out by    hydrogenation using a catalyst containing palladium; platinum,    rhodium or nickel in a suitable solvent such as acetic acid or an    alcohol e.g. ethanol or methanol at atmospheric or elevated pressure    and at a reaction temperature between +20° C. and +120° C.-   (xii) Halogenation of the compound of formula XIX, wherein R₂ is    C₁₋₃alkyl and halo is halogeno as defined hereinbefore, to obtain a    compound of formula XX may be performed by aromatic electrophilic    substitution using a suitable halogenation agent such as Br₂, Cl₂,    I₂, ICl, or SO₂Cl₂ or another suitable halogenation agent such as    N-bromosuccinimid in an appropriate solvent e.g. acetonitrile,    acetic acid, HCl/ethanol or water with or without a suitable base    e.g. alkali metal acetate such as sodium acetate and at a reaction    temperature between −20° C. and room temperature.-   (xiii) Nitration of a compound of formula XIV wherein halo is    halogeno, as defined hereinbefore, to obtain a compound of formula    XXI, may be carried out by aromatic electrophilic substitution using    a suitable nitration reagent such as potassium nitrate, nitric acid    and sulphuric acid in a suitable solvent such as acetic acid, acetic    anhydride, sulphuric acid or water at a reaction temperature between    −20° C. and room temperature.    Methods of Preparation of End Products

Another object of the invention is a process for the preparation of acompound of general formula I, as a free base or a pharmaceuticallyacceptable salt thereof, by

i)

Reacting a compound of formula B (IV, VI, VII, XI), wherein L⁴ is aleaving group L¹ or. SCH₃, with a compound of formula C, to obtain acompound of formula I, and R¹, R², R³, m and n are as defined in generalformula I

Thus, the reaction of the process may be carried out in an appropriatesolvent such as an ether e.g. tetrahydrofuran or 1,4-dioxan, an aromatichydrocarbon solvent such as toluene, or a dipolar aprotic solvent suchas NDN-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidin-2-one or dimethyl sulphoxide and the reaction isconveniently effected at a temperature in the range of +10 to +150° C.,preferably in the range of +20 to +90° C. The reaction is advantageouslyeffected in the presence of a base. Such a base may be an organic aminebase such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethylamine, morpholine, N-methylmorpholine ordiazabicyclo[5.4.0]undec-7-ene, tetramethylguanidine, an alkali metal oralkaline earth metal carbonate or hydroxide such as sodium carbonate,potassium carbonate, calcium carbonate, sodium hydroxide or potassiumhydroxide. Alternatively, such a base is an alkali metal hydride such assodium hydride, or an alkali metal or alkaline earth metal amide such assodium amide, sodium bis(trimethylsilyl)amide, potassium amide orpotassium bis(trimethylsilyl)amide. When it is desired to obtain theacid salt, the free base may be treated with an acid, using aconventional procedure.ii).Hydrolysis of a compound of formula Ia, wherein R² is C₁₋₄alkoxycarbonylto obtain a compound of formula]_(b), wherein R² is carboxy and R¹, R³,m and n are as defined in general formula I.

This reaction may be carried out under acidic conditions using acidssuch as sulfuric acid, hydrochloride or hydrobromide in a suitablesolvent e.g. water, ethanol, methanol or mixtures thereof and thereaction may occur between +20° C. and +100° C. or under basicconditions using bases such as sodium hydroxide or potassium hydroxidein a suitable solvent e.g. water, ethanol, methanol or mixtures thereofand the reaction may occur between +20° C. and +100° C.iii)

Amidation of a compound of formula Ib, wherein R² is carboxy to obtain acompound of formula Ic, wherein R² is R⁴X¹ and X¹ is CONR⁵R⁶ and R¹, R³,R⁴, R⁵, R⁶, m and n are as defined in general formula I

This reaction may be performed by activation of a compound of formulaIb, wherein R² is carboxy, by treating the compound with couplingreagents e.g. 1-[3-(dirhethylamino)propyl]-3-ethylcarbodidehydrochloride and 1-hydroxybenzotriazole hydrate orhydroxybenzimidazole, 1,3-dicyclohexylcarbodiimide and1-hydroxybenzotriazole hydrate, 1,1′-carbonyldiimidazole orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroriumhexafluorophosphate, or using an acyl halide reagent e.g. cyanuricchloride, oxalyl chloride, thionyl chloride orbromotrispyrrolidinophosphonium hexafluorophosphate, followed bytreatment with the appropriate amine with or without the presence ofN,N-dimethylaminopyridine, in a suitable solvent such asN,N-dimethylformamide, tetrahydrofuran, N-methylpyrrolidone, methylenechloride or chloroform at a reaction temperature between 0° C. and +80°C.

EXAMPLES

The invention will now be illustrated by the following non-limitingExamples.

Example 1 7-(2-Morpholin-4-yl)ethoxy)-3H-quinazolin-4-one

A mixture of sodium hydride (12.7 g, 0.317 mol, 60% oil dispersion) anddimethyl sulfoxide (60 mL, 0.84 mol) was heated at 75° C. After 30 minthe hydrogen gas evolution had ceased and the reaction was cooled toroom temperature.

4-(2-Hydroxyethyl)morpholine (48 mL, 0.40 mol) was added portionwise tothe reaction mixture. After stirring for 30 min,7-fluoro-3H-quinazolin-4-one (13.0 g, 79.2 mmol; described in RewcastleG. et al J. Med. Chem, 1996, 39, 4, 918-928) was added and the reactionsolution was heated for 3 h at 150° C. The reaction mixture was cooledto room temperature and the resulting syrup was dissolved in ethylacetate (500 mL) and triturated with diethyl ether (2 L). The solid wasfiltered off under a nitrogen atmosphere and washed several times withdiethyl ether to obtain the crude product as a powder. The crude productwas purified by flash chromatography (500 g silica gel column toppedwith a layer of celite) using methanol/methylene chloride systems(methanol/methylene chloride: 7:93 (4 L); 10:90 (2 L); 15:85 (2 L);25:75 (4 L)) as stepwise gradient eluents. The fraction containing theproduct was concentrated to dryness, triturated with acetone andfiltered to give 21.8 g (65% yield) of the title compound as anoff-white solid: MS (AP+) m/z 276.0 (M⁺+1).

Example 2 4-Chloro-7-[(2-morpholinyl)ethoxy]quinazoline

Oxalyl chloride (4.55 mL, 52 mmol) was added dropwise to a suspension of7-(2-morpholin-4-yl)ethoxy)-3H-quinazolin-4-one (11.9 g, 43.3 mmol) inmethylene chloride (175 mL) followed by dropwise addition ofN,N-dimethylformamide (1.5 mL). The reaction mixture was heated for 2 hat reflux. The solvent was removed in vacuo and the resulting solid wastriturated with diethyl ether. The pale yellow solid was filtered offunder nitrogen atmosphere to give 17.2 g (99% yield) of the titlecompound as a pale yellow powder: MS (AP+) mz/z 294.0 (M⁺+1).

Example 32-Hydroxy-3-[7-(2-morpholin-4-ylethoxy)quinazolin-4-yl]-1H-indole-5-carbonitrildihydrochloride

Sodium hydride (490 mg, 12.2 mmol, 60% oil dispersion) was washed withpetroleum ether (2×10 mL) and dried under vacuum anrd the obtainedmaterial was suspended in anhydrous N,N-dimethylformamide (5 mL) and5-cyanooxindole (323 mg, 2.04 mmol) in N,N-dimethylformamide (3 mL) wasadded. The resulting suspension was stirred for 30 min at roomtemperature and 4-chloro-7-[(2-morpholin-4-yl)ethoxy]quinazoline (200mg, 0.68 mmol) in N,N-dimethylformamide (5 mL) was added. The reactionmixture was stirred for 1 h at room temperature. The reaction wasquenched with aqueous hydrochloric acid (5 mL, 1 M) andN,N-dimethylformamide was removed in vacuo. To the resulting syrup wasadded water (50 mL) and the mixture were stirred vigorously. The solidformed was filtered off and dried at 70° C. under vacuum over night. Thecrude product was refluxed in methanol for 15 min and the insolublematerial was filtered off and dried at 85° C. under vacuum over night togive 225 mg (68% yield) of the title compound as an orange powder: MS(AP—) m/z 413.9 (M−1); Anal. (C₂₋₃H₂₁N₅O₃×2HCl×0.1H₂O)C, H, N.

Example 4 Methyl2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylate

Sodium hydride (58 mg, 1.45 mmol, 60% in oil) was washed with petroleumether (3×5 mL) and dried in vacuo. The solid was suspended intetrahydrofuran (3 mL) and methyl 2-oxo-5-indolinecarboxylate (140 mg,0.73 mmol) in tetrahydrofuran (2 mL) and N-methylpyrrolidinone (2 mL)was added. The reaction mixture was stirred for 30 min at roomtemperature. A solution of 4-chloro-7-(2-methoxyethoxy)quinazoline (183mg, 0.77 mmol, described in WO 97/42187) in tetrahydrofuran (2 mL) andN-methylpyrrolidinone (1 mL) was added and the reaction mixture wasstirred for 1.5 h at room temperature. The solvent was removed in vacuoand 1 M hydrochloric acid was added. The precipitate formed was filteredoff and dried at 40° C. in vacuo over night to give 150 mg (99% yield)of the title compound as an orange solid: MS (AP+) nVz 394.2 (M⁺+1).

Example 52-Hydroxy-3-[7-(2-methoxyethloxy)quinazolin-4-yl]-1H-indole-5-carboxylicAcid

To a mixture of methyl2-hydroxy-3-[7-(2-methoxyethoxy)quinazolinIyl]-1H-indole-5-carboxylate(5.15 g, 13.1 mmol), methanol (100 mL) and water (50 mL), was addedaqueous sodium hydroxide (92 mL, 1 M) and the reaction mixture wasstirred at 40° C. over night. Methanol was removed in vacuo and thebasic aqueous layer was acidified with 1 M hydrochloric acid and stirredfor 30 min. The precipitate formed was filtered off, washed withhydrochloric acid (50 mL, 1 M) and water (2×50 mL) and dried in vacuo at50° C. over night. The crude product was stirred in methanol at roomtemperature over night. The solid was filtered off to give 4.23 g (85%yield) of the title compound as an orange solid: MS (AP+) m/z 380.3(M⁺+1).

Examples 6-11

General Method A

Stock solution A was prepared by dissolving2-hydroxy-3-[7-(2-methoxyethoxy)-quinazolin-4-yl]-1H-indole-5-carboxylicacid (2.0 g), (3-direthylaminopropyl)-3-ethylcarbodiimide hydrochloride(2.2 g) and hydroxybenzimiidazole (1.54 g) in N-methylpyrrolidinone (160mL). Stock solution B was prepared by dissolvingN,N-dimethylaminopyridine (2.8 g) in N-methylpyrrolidinone (40 mL). Theamidation reaction was performed by adding solution A (8 mL,corresponding to2-hydroxy-3-[7-(2-methoxyethoxy)-quinazolin-4-yl]-1H-indole-5-carboxylicacid: 100 mg, 0.26 mrol, 1 eq;(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride: 110 mg, 0.51mmol, 2.2 eq; hydroxybenzimidazole: 77 mg, 0.57 mmol, 2.2 eq) to areaction vessel containing the desired amine (0.4 mmol, 1.5 eq).Solution B (2 mL, corresponing to N,N-dimethylaminopyridine: 140 mg,1.14 mmol, 4.4 eq) was added and the resulting solution was stirred atroom temperature over night. The solvent was removed in vacuo to givethe crude product.

Example 62-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylicAcid [2-(1-Methylpyrrolidin-2-yl)ethyl]amide

The reaction was performed as described in method A using2-(2-aminoethyl)-1-methylpyrrolidine (0.06 mL, 0.40 mmol). The crudeproduct was triturated with acetonitrile. The solid was decanted andwashed with methanol/diethyl ether to give 36 mg (28% yield) of thetitle compound: MS (AP+) m/z 490.4 (M⁺+1).

Example 72-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylicAcid (Tetrahydrofuran-2-ylmethyl)amide

The reaction was performed as described in method A usingtetrahydro-2-furanylmethylamine (0.06 mL, 0.395 mmol). The crude productwas triturated with acetone and the solid was washed with hot methanolto give 19 mg (16% yield) of the title compound: MS (AP+) m/z 537.3(M⁺+1).

Example 82-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylicAcid (3-Morpholin-4-yl-propyl)amide

The reaction was performed as described in method A using3-(morpholin-4-yl)propanamine (0.06 mL, 0.395 mmol). The crude productwas triturated with acetonitrile and the solid was washed with hotmethanol to give 15 mg (12% yield) of the title compound: MS (AP+) m/z506.3 (M⁺+1).

Example 92-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylicAcid (4-Phenylbutyl)amide

The reaction was performed as described in method A using4-phenylbutylainine (0.06 mL, 0.395 mmol). The crude product wastriturated with acetone and the solid was washed with hot methanol togive 38 mg (29% yield) of the title compound: MS (AP+) m/z 511.3 (M⁺

Example 102-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxy licAcid [2-(1H-Imidazol-4-yl)ethyl]amide

The reaction was performed as described in method A using2-(1H-imidazol-4-yl)ethylamine dihydroehloride (73 mg, 0.395 mmol). Thecrude product was triturated with acetonitril. The solid decanted andtriturated with acetonitrile/methanol/diethyl ether and washed with hotrmethanol to give 26 mg (21% yield) of the title compound: MS (AP+) m/z473.3 (M⁺+1).

Example 11 7-[2-(2-Methoxyethoxy)ethoxy]-3H-quinazolin-4-one

Dimethyl sulfoxide (6.9 mL, 97 mmol) was added to sodium hydride (1.46g, 36.6 mmol) and the formed foamy suspension was heated at 75° C. for30 min until the gas evolution had ceased. The formed green cloudysolution was cooled to room temperature and 2-(2-methoxyethoxy)ethanol(5.44 mL, 45.7 mmol) was added slowly and the mixture was stirred for 30min. 7-Fluoro-3H-quinazolin-4-one (1.5 g, 9.14 mmol; described inRewcastle G. et al J. Med. Chem, 1996, 39, 4, 918-928) was added andheated at 150° C. for 4 h. The reaction mixture was cooled and dilutedwith ethyl acetate (60 mL) followed by the addition of diethyl ether(200 mL). The formed precipitate was filtered under nitrogen atmosphereand washed with diethyl ether. The hygroscopic crude product waspurified on a silica gel column using chloroform/methanol (20:1), as theeluent to give 1.2 gram (50% yield) of the title compound as a slightlycoloured solid: MS (TSP) m/z 265 (M³⁰+1).

Example 12 4-Chloro-7-[2-(2-methoxyethoxy)ethoxy]quinazoline

To a solution of 7-[2-(2-methoxyethoxy)ethoxy]-3H-quinazolin-4-one (0.86g, 3.25 mmol) in methylene chloride (15 mL) was added oxalyl chloride(0.34 mL, 3.9 mmol) and dimethyl sulfoxide (0.1 mL) and the reaction washeated at reflux for 2 h. The solvent was evaporated in vacuo and theresidue was washed with diethyl ether and dried in vacuo to give 0.9gram of the title compound as a semi-solid: MS (TSP) m/s 283 (M⁺+1).

Example 132-Hydroxy-3-{7-[2-(2-methoxyethoxy)ethoxy]quinazolin-4-yl}-1H-indole-5-carbonitrileHydrochloride

To a suspension of sodium hydride (0.52 g, 12.8 mmol, pre-washed withhexane) in tetrahydrofuran (6 mL) was added a solution of5-cyanooxindole (1 g, 6.4 mmol) in tetrahydrofuran (11 mL) and1-methyl-2-pyrrolidone (11 mL). The mixture was stirred for 30 min undernitrogen atmosphere. 4-Chloro-7-[2-(2-methoxyethoxy)ethoxy]quinazoline(0.9 g, 3.2 mmol) dissolved in 1-methyl-2-pyrrolidone (10 mL) was addeddropwise and the dark red solution was stirred at ambient temperaturefor 1.5 h. The solvent was evaporated in vacuo until approximately 10 mLof 1-methyl-2-pyrrolidone remained, whereupon aqueous hydrochloric acid(1 M, 25 mL) was added. The formed precipitation was filtered and washedwith 1 M hydrochloric acid. Drying in vacuo afforded 1.1 gram (78%yield) of the title compound as an orange solid: MS (TSP) m/s 405 (M⁺+1)

Example 143-[7-(2-Inidaol-1-yl-ethoxy)-6-methoxyquinazolin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-sulfonamideAcetate

Sodium hydride (59 mg, 1.48 mmol, pre-washed with pentane) was added toa suspension of 2-oxo-2,3-dihydro-1H-indole-5-sulfonamide (313 mg, 1.48mmol; described in WO 9742187) in NN-dimethylformamide (2.5 mL). Afterstirring 30 min at ambient temperature,4-chloro-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline (150 mg, 0.49mmol; described in WO 97/42187) was added followed by dimethyl sulfoxide(0.5 mL). After stirring for 10 min at ambient temperature, the mixturewas stirred at 60° C. for 2 h. The mixture was poured onto diethylether/water (1:1, 100 mL). The organic layer was separated and theaqueous layer was adjusted to pH 6.3 (5 M HCl_((aq))). The precipitatewas filtered, washed with water, followed by diethyl ether, methylenechloride and dried in vacua. The solid was dissolved in water adjustedto pH 1.5 (5 M HCl_((aq))) and the solution was purified by preparativeC18 HPLC eluting with methanol/water (1:9, containing 1% acetic acid)followed by 15:85 followed by 4:6. The fractions containing the expectedproduct were combined, concentrated and the product was freeze-dried anddried in vacuo at 60° C. for 48 h to give 133 mg (54% yield) of thetitle compound: EIMS m/z 480 (M⁺).

Example 156-Chloro-3-[7-(3-morpholin-4-yl-pronoxy)quinazolin-4-yl]-1,3-dihydro-indol-2-onehydrochloride

6-Chlorooxindole (383 mg, 2.28 mmol) was added to a suspension of sodiumhydride (92 mg, 2.28 mmol) in N,N-dimethylformamide (3 mL). Afterstirring for 20 min at ambient temperature,4-chloro-7-(3-(morpholin-4-yl)propoxy)quinazoline (233 mg, 0.76 mmol;described in WO 97/42187) in N,N-dimethylformamide (3 mL) was added. Themixture was stirred at 70° C. for 45 min. After cooling, the volatileswere removed in vacuo and the residue was partitioned between ethylacetate and water. The pH of the aqueous layer was adjusted to 8.4 with2 M HCl. The organic layer was separated and washed with brine, dried(MgSO₄) and evaporated. The residue was purified by columnchromatography eluting with methanol/methylene chloride, 5:95, followedby 10:90. The fractions containing the expected product were combinedand evaporated. The residue was dissolved in methylene chloride (10 mL)and methanol (3 mL) and HCl in diethyl ether (3.8 M, 0.5 mL) was added.The precipitate was filtered, washed with diethyl ether and dried invacuo to give 141 mg (34% yield) of the title compound. ESI-MS 439(M⁺+1).

Example 166-Bromo-3-[6-methoxy-7-(3-morpholin-4-ylpropoxyy)quinazolin-4-yl]-1,3-dihydro-indol-2-oneDihydrochloride

Sodium hydride (71 mg, 1.78 mmol, 60% in oil) was added to a solution of6-bromooxindole (126 mg, 0.59 mmol) in N,N-dimethylformamide (3 mL).After stirring for 15 min at ambient temperature,4-chloro-6-methoxy-7-(3-(morpholinX yl)propoxy)quinazoline (200 mg, 0.59mmol; described in WO 97/42187) in N,N-dimethylformamide (4 mL) andtetrahydrofuran (4 mL) was added. After stirring at 60° C., for 2.5 h,water was added and the volatiles were removed in vacuo. Water (50 mL)was added and the pH of the solution was adjusted to 8.5 with aqueoushydrochloric acid (2 M). Ethyl acetate was added. The organic layer wasseparated, washed with brine, dried (MgSO₄) and evaporated. The residuewas purified by column chromatography eluting with methanol/methylenechloride, 5:95, followed by 8:92. The fractions containing the expectedproduct were combined and evaporated. The solid was dissolved inmethylene chloride (10 mL) and methanol (3 mL) and 3.8 M HCl in diethylether (1 mL) was added. The solution was concentrated and the solid wasfiltered to give 70 mg (23% yield) of the title compound: ESI-MS:513-515 (M⁺+1).

Example 17 6-Bromo-3-quinazolin-4-yl-1,3-dihydroindol-2-oneHydrochloride

To a suspension of sodium hydride (117 mg, 2.9 mmol, pre-washed withpentane) in N,N-dimethylformamide (1.5 mL was added a solution of6-bromooxindole (618 mg, 2.9 mmol) in N,N-dimethylformamide (4 mL).After stirring 15 min at ambient temperature, 4-chloroquinazoline (618mg, 2.9 mmol) in NN-dimethylformamide (4 mL) was added and the mixturewas stirred at 80° C. for 45 min. After cooling, the volatiles wereremoved under vacuum and the residue was suspended in water and the pHwas adjusted to 7 with aqueous hydrochloric acid (2 M). The precipitatewas filtered, washed with water and dried over P₂O₅ over night. Thesolid was dissolved in methanol/methylene chloride and adsorbed onsilica and purified by column chromatography, eluting with methylenechloride/methanol, 99:1, followed by 98:2 and 95:5. The fractionscontaining the expected product were combined and evaporated. Theproduct was purified a second time on silica eluting with methylenechloride/methanol, 97:3, followed by 95:5. The solid was the suspendedin methylene chloride/methanol, 1:1, and HCl in diethyl ether (3.6 M, 1mL) was added. The precipitate was filtered, washed with diethyl etherand dried in vacuo to give 270 mg (74% yield) of the title compound:ESI-MS 340-342 (M⁺+1)

Example 186-Bromo-3-{6-imethoxy-7-[2-(2-methoxyethoxy)ethoxy]quinazolin-4-yl}-1,3-dihydroindol-2-onehydrochloride

To a suspension of sodium hydride (48 mg, 1.2 mmol, pre-washed withpentane) in dimethyl sulfoxide (1 mL) was added a solution of6-bromooxindole (255 mg, 1.2 mmol) in dimethyl sulfoxide (2 mL). Afterstirring for 15 min,6-methoxy-7-[2-(2-methoxyethoxy)ethoxy]-4-(methylthio)quinazoline (130mg, 0.4 mmol; described in WO 97/42187) was added. The mixture wasstirred at 100° C. for 3 h. After cooling, the mixture was partitionedbetween ethyl acetate and water. The pH of the aqueous layer wasadjusted to 7 with aqueous hydrochloric acid (2 M). The organic layerwas separated, washed with brine, dried (MgSO₄) and evaporated. Theresidue was purified by column chromatography eluting with methylenechloride/methanol, 93:7. The fractions containing the expected productwere combined and evaporated. The solid was dissolved in methylenechloride/methanol and HCl in diethyl ether (3.8 M, 2 mL) was added. Thesolution was concentrated under vacuum and the solid was filtered,washed with diethyl ether and dried in vacuo to give 109 mg (52% yield)of the title compound: ESI-MS 488-490 (M⁺+1).

Example 193-7-[2-(2-Morpholin-4-yl-ethoxy)ethoxy]quinazolin-4-yl-2-oxo-2,3-dihydro-1H-indole-5-carbonitrileHydrochloride

A solution of 5-cyanooxindole (240 mg, 1.5 mmol) was added portion wiseto a suspension of sodium hydride (60 mg, 1.5 mmol, pre-washed withpentane) in dimethyl sulfoxide (2 mL). After stirring for 30 min atambient temperature,4-(methylthio)-7-[2-(2-morpholin-4-ylethoxy)ethoxy]quinazoline (175 mg,0.5 mmol) was added. The mixture was stirred at 100° C. for 2 h. Aftercooling, water was added and the pH was adjusted to 7 with aqueoushydrochloric acid (2.5 M). The precipitate was filtered, washed withwater and dried over night in vacuo over P₂O₅. The solid was purified bycolumn chromatography eluting with methanol/methylene chloride, 5:95,followed by 10:90. The fractions containing the expected product werecombined and evaporated. The solid was dissolved in methanol/methylenechloride, 1:1, and HCl in diethyl ether (3.5 M, 0.5 mL) was added,followed by diethyl ether. The precipitate was filtered, washed withdiethyl ether and dried in vacuo to give 155 mg (53% yield) of the titlecompound: ESI-MS 460 (M⁺+1).

Example 204-(Methylthio)-7-[2-(2-morpholin-4-ylethoxy)ethoxy]quinazoline

Diethyl azodicarboxylate (2.46 ml, 15.6 mmol) was added dropwise to asuspension of 4(methylthio)-7-hydroxyquinazoline (1.2 g, 6.25 mmol;described in WO 99/10349), triphenylphosphine (4.09 g, 15.6 mmol) and2-(2-morpholin-4 ylethoxy)ethanol (1.42 g, 8.12 mmol; described in J.Med. Chem,. 1994, 37, 15, 2285-2291) in methylene chloride (30 mL).After stirring 1.5 h at ambient temperature, the volatiles were removedin vacuo. The residue was dissolved in ethyl acetate/methylene chloride,filtered and poured onto a column of silica. The product was eluted withmethylene chloride/methanol, 97:3, followed by 95:5. The fractionscontaining the expected product were combined and evaporated. Theresidue was triturated with diethyl ether and the solid was filtered anddried in vacuo to give 1.1 g (49% yield) of the tide compound: ESI-MS350 (M⁺+1).

Example 216-Chloro-3-{7-[2-(2-methoxyethoxy)ethoxy]quinazolin-4-yl}-1,3-dihydro-indol-2-oneHydrochloride

6-Chlorooxindole (285 mg, 1.7 mmol) was added to a suspension of sodiumhydride (102 mg, 2.55 mmol, pre-washed with pentane) in dimethylsulfoxide (4 mL). After stirring 30 min at ambient temperature, asolution of 7-[2-(2-methoxyethoxy)ethoxy]-4-(methylthio)quinazoline (250mg, 0.85 mmol; described in WO 99/10349) in dimethyl sulfoxide (2 mL)was added and the mixture was stirred at 90° C. for 1 h. The mixture waspoured onto water (20 mL) and aqueous hydrochloric acid (2 M, 5 mL). Theprecipitate was filtered, washed with water and dried over P₂O₅. Thesolid was triturated with diethyl ether, filtered, washed with diethylether and dried in vacuo over night. The solid was dissolved inmethylene chloride/methanol and HCl in diethyl ether (3.8 M) was added.The solution was concentrated and the solid was filtered and dried invacuo to give 231 mg (60% yield) of the title compound: ESI-MS 414-416(M⁺+1).

Example 223-{7-[2-(2-Methoxyethoxy)ethoxy]quinazolin-4-yl}-1,3-dihydroindol-2-oneHydrochloride

The compound was prepared as descirbed for Example 29 using7-[2-(2-methoxyethoxy)ethoxy)-4-(methylthio)quinazoline (257 mg, 1.93mmol; described in WO 99/10349) and oxindole (190 mg, 0.64 mmol) to give191 mg (70% yield) of the title compound as the hydrochloride: ESI-MS380 (M+1).

Example 233-{7-[2-(4-Acetylpiperazin-1-yl)ethoxy]quinazolin-4-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrileHydrochloride

A solution of 5-cyanooxindol (260 mg, 1.64 mmol) in dimethyl sulfoxide(2 mL) was added to a suspension of sodium hydride (66 mg, 1.64 mmol,pre-washed with pentane) in dimethyl sulfoxide (0.8 mL). The mixture wasstirred for 20 min at ambient temperature and7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-methylthioquinazoline (190 mg,0.55 mmol) was added and stirring was continued for 3 h at 100° C. Themixture was poured onto a saturated aqueous solution of ammoniumchloride and ethyl acetate was added. The formed precipitate wasfiltered and the filtrate was extracted with ethyl acetate. The ethylacetate layers were dried (Na₂SO₄) and evaporated to give a solid. Thesolid and the initial precipitate were dissolved in methylenechloride/methanol and adsorbed on silica. The product was purified bycolumn chromatography eluting with methylene chloride/methanol, 9:1. Thefractions containing the expected product were combined and evaporated.The oily residue was dissolved in methylene chloride/methanol, 1:1, and3.8 M HCl in diethyl ether (2 mL) was added. The solution wasconcentrated and the precipitate was filtered, washed with diethyl etherand dried in vacuo to give 189 mg (63% yield) of the title compound:ESI-MS 457 (M⁺+1).

Example 24 7-[2-(4-Acetylpiperazin-1-yl)ethoxy]-4-methylthioquinazoline

7-(2-Bromoethoxy)₄-methylthioquinazoline (250 mg, 0.83 mmol) andacetylpiperazine (225 mg, 1.75 mmol) was stirred at 120° C. for 10 min.The solid was dissolved in ethyl acetate and water and the pH of theaqueous layer was adjusted to 9 with 2 M NaOH_((aq)). The organic layerwas separated and the aqueous layer was extracted with ethyl acetate.The organic layers were combined, washed with brine, dried (MgSO₄) andevaporated and the residue was purified by column chromatography elutingwith methylene chloride/methanol, 92:8, to give 226 mg (78% yield) ofthe title compound: ESI-MS 347 (M⁺+1).

Example 255-Chloro-3-{7-[2-(2-methoxyethoxy)ethoxy]quinazolin-4-yl}-1,3-dihydro-indol-2-oneHydrochloride

5-Chlorooxindol (230 mg, 1.14 mmol) was added to a suspension of sodiumhydride (92 mg, 2.28 mmol; 60% in oil) in dimethyl sulfoxide (4 mL).After stirring 15 min at ambient temperature,7-[2-(2-methoxyethoxy)ethoxy]-4-(methylthio)quinazoline (223 mg, 0.76mmol, described in WO 99/10349) was added. The mixture was stirred at110° C. for 1 h and then poured onto water (75 mL). The pH was adjustedto 8 with aqueous hydrochloric acid (2 M). The precipitate was filtered,washed with water and dried in vacuo. The solid was dissolved inmethylene chloride/methanol and HCl in diethyl ether (3.8 M, 2 mL) wasadded. The volatiles were removed in vacuo to give 233 mg (67% yield) ofthe title compound: ESI-MS 414 (M⁺+1).

Example 263-{7-[2-(4-Butyrylpiperazin-1-yl)ethoxy]quinazolin-4-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrileHydrochloride

5-Cyanooxindol (221 mg, 1.4 mmol) in dimethyl sulfoxide (1.7 mL) wasadded to a suspension of sodium hydride (56 mg, 1.4 mmol, pre-washedwith pentane) in dimethyl sulfoxide (0.8 mL). After stirring 10 min atambient temperature,7-[2-(4-butyrylpiperazin-1-yl)ethoxy]4-(methylthio)quinazoline (175 mg,0.47 mmol) was added and the mixture was stirred at 100° C. for 3 h.After cooling, the mixture was partitioned between ethyl acetate andwater and the pH was adjusted to 8.2 with aqueous hydrochloric acid (2M). The precipitate was filtered, washed with water followed by ethylacetate. The aqueous layer was extracted with ethyl acetate and theethyl acetate layers were combined and evaporated to give a solid. Thesolid and the first precipitate were combined, dissolved in ethylacetate and methanol and adsorbed on silica. The product was purified bycolumn chromatography eluting with methylenechloride/acetonitrile/methanol, 60:42:8 followed by 70:20:10. Thefractions containing the expected product were combined and evaporated.The solid was dissolved in methylene chloride/methariol and 3.8 M HCl indiethyl ether was added. The volatiles were removed under vacuum and thesolid was filtered, washed with diethyl ether and dried in vacuo to give195 mg (74% yield) of the title compound: ¹HNMR (MSO-d6, TFA-d) δ 0.92(t, 3H), 1.55 (m, 2H), 2.38 (dd, 2H), 2.9-3.7 (br m, 6H), 3.72 (br s,2H), 4.05-4.2 (br s, 1H), 4.44.6 (br s, 1H), 4.65 (m, 2H), 7.1 (d, 1H),7.25 (d, 1H), 7.38 (dd, 1H), 7.5 (d, 1H), 8.1 (s, 1H), 8.65 (d, 1H), 8.7(s, 1H); ESI-MS 485 (M⁺+1).

Example 27 7-(2-Bromoethoxy)-4-(methylthio)quinazoline

7-Hydroxy-4-(methylthio)quinazoline (1 g, 5.2 mmol; described in WO99/10349), 1,2-dibromoethane (673 μL, 7.8 mmol) and potassium carbonate(2.1 g, 15 mmol) in N,N-dimethylformamide (15 mL) was stirred for 6 h atambient temperature. Additional 1,2-dibromoethane (224 μL) was added andstirring was continued over night. The solid was filtered and washedwith ethyl acetate. The filtrate was washed with water, brine, dried(MgSO₄) and evaporated. The residue was purified by columnchromatography eluting with methylene chloride/methanol, 98:2. Thefraction containing the expected product were combined and evaporated togive 179 mg (11% yield) of the title compound: ESI-MS 299-301 (M⁺+1).

Example 28 7-[2-(4-Butyrylpiperazin-1-yl)ethoxy]-4-(methylthiocinazoline

7-(2-Bromoethoxy)+(methylthio)quinazoline (0.55 g, 1.8 mmol) and1-butyrylpiperazine (0.6 g, 3.86 mmol) was stirred at 120° C. Themixture was then diluted with water and methylene chloride and the pHwas adjusted to 9 with 2 N aqueous Na₂CO₃. The organic layer wasseparated and the aqueous layer was further extracted with methylenechloride. The organic layer was combined, washed with brine, dried(MgSO₄) and evaporated. The residue was purified by columnchromatography eluting with methylene chloride/methanol, 94:6. Thefractions containing the expected product were combined and evaporatedto give 461 mg (68% yield) of the title compound: ESI-MS 375 (M⁺+1).

Example 293-{7-[2-(4-Acetylpiperazin-1-yl)-2-oxoethoxy]quinazolin-4-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrileHydrochloride

A solution of 5-cyanooxindol (329 mg, 2.1 mmol) in dimethyl sulfoxide (3mL) was added to a suspension of sodium hydride (83 mg, 2.1 mmol, 60% inoil) in dimethyl sulfoxide (1 mL). After stirring 10 min at ambienttemperature,7-[2-(4-acetylpiperazin-1-yl)-2-oxoethoxy]4-(methylthio)quinazoline (250mg, 0.69 mmol) was added. After stirring at 100° C. for 2 h, the mixturewas poured onto saturated aqueous ammonium chloride. The precipitate wasfiltered, washed with water followed by ethyl acetate and dried invacuo. The solid was dissolved in methylene chloride/methanol and driedover Na₂SO₄. After filtration, the filtrate was concentrated and theresidue was adsorbed onto silica. The product was purified by columnchromatography, eluting with methylene chloride/methanol, 93:7, followedby 90:10. The fractions containing the expected product were combinedand evaporated. The solid was dissolved in methylene chloride/methanoland 3.8 M HCl in diethyl ether was added (2 mL). The volatiles wereremoved in vacuo and the solid was filtered, washed with diethyl etherand dried in vacuto to give 189 mg (52% yield) of the title compound:ESI-MS 471 (M⁺+1).

Example 307-[2-(4-Acetyluiperazin-1-yl)-2-oxoethoxy]-4-(methylthio)quinazoline

7-Hydroxy-4-methylthioquinazoline (600 mg, 3.12 mmol; described in WO99/10349) was added to a suspension of sodium hydride (131 nmg, 3.28mmol, prewashed with pentane) in N,N-dimethylformamide (7 mL). Afterstirring for 15 min, 1-acetyl-4-bromoacetylpiperazine (855 mg, 3.43mmol; described in Chem. Europ. J., 2001, 7, 1, 288-296) was added andthe mixture was stirred at 50° C. for 1 h. The mixture was poured ontowater containing some ethyl acetate. The precipitate was filtered,washed with water followed by diethyl ether and dried over night invacuo over P₂O₅ to give 975 mg (99% yield) of the title compound: ESI-MS361 (M⁺+1).

Example 313-{7-[4-(4-Acetylpiperazin-1-yl)-4-oxobutoxy]quinazolin-4-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrileHydrochloride

The compound was prepared as described for Example 29 using5-cyanooxindole (221 mg, 1.4 mmol) and7-[4-(4-acetylpiperazin-1-yl)-4-oxobutoxy]4-(methylthio)quinazoline (181mg, 0.466 mmol). After extraction and purification by columnchromatography eluting with methylene chloride/acetonitrile/methanol,60:32:8, followed by 70:20:10 and trituation with HCl in diethyl etherto give 165 mg (62% yield) of the title compound: ESI-MS 499 (M⁺+1).

Example 32 1-Acetyl-4-(4-chlorobutanoyl)piperazine

A solution of 4-chlorobutanoyl chloride (1.54 mL, 13.7 mmol) inmethylene chloride (5 mL) was added dropwise over 30 min to a solutionof acetylpiperazine (1.6 g, 12.5 mmol) in methylene chloride (25 mL)cooled at −70° C. After stirring 1 h at −70° C. and 2.5 h at ambienttemperature, the mixture was poured onto a saturated solution ofammonium chloride and the pH of the aqueous layer was adjusted to 8 withsolid Na₂CO₃. The organic layer was separated and the aqueous layer wasextracted with methylene chloride. The organic layers were combined,dried (MgSO₄) and evaporated. The residue was purified by columnchromatography eluting with methylene chloride/methanol, 98:2, followedby 96:2 to give 2.51 g (86% yield) of the title compound: ESI-MS 233-235(M⁺+1).

Example 337-[4-(4-Acetylpiperazin-1-yl)-4-oxobutoxy]-4-(methylthio)quinazoline

7-Hydroxy-4-(methylthio)quinazoline (600 mg, 3.12 mmol; described in WO99/10349) was added to a suspension of sodium hydride (131 mg, 3.28mmol, pre-washed with pentane) in N,N-dimethylformamide(7 mL). Afterstirring for 15 min, a solution of1-acetyl-4-(4-chlorobutanoyl)piperazine (1.1 g, 3.43 mmol) inN,N-dimethylformamide (2 mL) was added. The mixture was stirred for 4 hat 50° C. and 1 h at 70° C. The mixture was poured onto a saturatedaqueous solution of ammonium chloride and extracted with ethyl acetate.The organic layer was dried (MgSO₄), filtered and evaporated. Theresidue was purified by column chromatography eluting with methylenechloride/acetonitrile/methanol, 60:39:1, to give 400 mg (33% yield) ofthe title compound: ESI-MS 389 (M⁺+1).

Example 346-Fluoro-3-[7-(3-morpholin-4-ylprooxy)quinazolin-4-yl]-1,3-dihydro-indol-2-onedihydrochloride

To a suspension of sodium hydride (36 mg, 1.5 mmol, pre-washed withpentane) in dimethyl sulfoxide (2 mL) was added 6-fluorooxindole (226mg, 1.5 mmol). The mixture was stirred 30 min at ambient temperature and4-methylsulfanyl-7-(3-morpholin-4-ylpropoxy)quinazoline (182 mg, 0.5mmol; described in WO 97/42187) was added. The mixture was stirred at80° C. for 1.5 h and 6-fluorooxindole (76 mg, 0.5 mmol) was furtheradded. The mixture was stirred at 80° C. for 30 min. After cooling themixture was poured onto a column of silica and was eluted with methylenechloride/methanol (gradient from 100->0 to 94->6). The fractionscontaining the expected product were combined and concentrated. 3.8 MHCl in diethyl ether (2 mL) was added and the volatiles were removed invacuo. The solid was filtered, washed with diethyl ether and dried invacuo to give 52 mg (34% yield) of the title compound: ¹HNMR (DMSO-d6,TFA-d 2.2-2.35 (m, 2H), 3.1-3.2 (m, 2H), 3.3-3.4 (m, 2H), 3.51 (d, 2H),3.75 (dd, 2H), 4.02 (d, 2H), 4.3 (dd, 2H), 6.72-6.85 (m, 2H), 7.22 (s,1H), 7.3 (d, 1H), 7.68 (m, 1H), 8.42 (d, 1H), 8.8 (s, 1H).

Example 357-Fluoro-3-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]-1,3-dihydroindol-2-oneDihydrochloride

A stirred solution of 7-fluorooxindole (570 mg, 3.77 mmol) inN,N-dimethylformamide (15 mL) was degassed by subjecting it to severalcycles of vacuum and argon and stirred in an argon atmosphere whilstsodium hydride (175 mg, 4.38 mmol, 60% dispersion in oil) was added inone portion. After stirring for a further 30 min,4-chloro-6-methoxy-7-(3-(4-morpholinyl)propoxy)quinazoline (420 mg, 1.24mmol; described in WO 97/42187) was added, the reaction mixture stirredat 90° C. for 1 h and allowed to cool to room temperature. The solventwas evaporated in vacuo and the residue absorbed onto silica from amethylene chloride/methanol, 95:5, solvent mixture. The product waspurified by column chromatography eluting initially with methylenechloride/methanol, 95:5, and then with methylene chloride/methanol,90:10. After evaporation of the solvent, the formed solid was trituratedwith acetone, filtered and dried to give 220 mg (39% yield) of the titlecompound: mp 211-214° C.; ESI-MS 453 (M⁺+1).

Example 366-Bromo-3-[7-(2-imidazol-1-ylethoxy)-6-methoxyquinazolin-4-yl]-1,3-dihydroindol-2-oneDihydrochloride

7-(2-Imidazol-1-yl-ethoxy)-6-methoxy-3H-quinazolin-4-one (300 mg, 1.05mmol, described in WO 97/42187) and thionyl chloride (10 mL) containingN,N-dimethylformamide (5 drops) was refluxed for 1 h. The volatiles wereremoved in vacuo and the residue was dissolved in ethyl acetate. Theorganic layer was washed with aqueous sodium bicarbonate and dried(MgSO₄). The 4-chloroquinazoline was used in the next step withoutfurther purification. Sodium hydride (126 mg, 3.15 mmol, 60% in oil) wasadded to a suspension of 6-bromooxindole (660 mg, 3.15 mmol) inN,N-dimethylformamide (25 mL) and the 4-chloroquinazoline previouslyprepared was added dropwise and the mixture was stirred at 90° C. for 2h. After cooling, the mixture was worked-up as described for Example 44and the residue was purified by column chromatography eluting withmethylene chloride followed by methylene chloride/methanol/sat.NH_(3(aq)), 100:10:1. The fractions containing the expected product werecombined and evaporated. The solid was dissolved in methylenechloride/methanol, 1:1, and 1 M hydrogen chloride in diethyl ether (5mL) was added. The solid was filtered, washed with diethyl ether anddried in vacuo to give 225 mg (46% yield) of the title compound: EIS-MS480 (M⁺+1).

Example 373-[7-(2-Imidazol-1-ylethoxy)-6-methoxyquinazolin-4-yl]-2-oxo-2,3-dihydro-1H-indole-6-carbonitrileDihydrochloride

The compound was prepared as described for Example 44 using6-methoxy-7-(2-(imidazol-1-yl)ethoxy)-4-chloroquinazoline and6-cyanooxindole to give 160 mg of the title compound: EIS-MS 427 (M⁺+1).

Example 38 2-Oxo-2,3-dihydro-1H-indole-5-carboxylic Acid Dimethylamide

To a solution of 2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid (1.36 g,7.68 mmol; described in Sun, L. J. Med. Chem., 1999, 42, 5120) inN,N-dimethylformamide (25 mL) was added 1,1′-carbonyldiimidazole (1.24g, 7.68 mmol), and the mixture was heated at 70° C. under nitrogen for15 min. The solution was allowed to cool for 25 min, and dimethylamine(40% in water, 1.1 mL, 8.44 mmol) was added. The reaction mixture wasstirred at room temperature over night. The solvent was removed invacuo, and the residual oil was partitioned between chloroform and anaqueous hydrochloric acid solution (2 M). The aqueous layer wasextracted several times with chloroform. The combined organic layerswere dried (MgSO₄), and the solvent was removed in vacuo. The crudeproduct was purified by column chromatography on silica usingchloroform/ethanol, 95:5, as the eluent affording 0.69 g (44% yield) ofthe title compound as a pale pink solid: mp 147.2-147.5° C.; MS (ESP)m/z 205 (M⁺+1).

Example 39 2-Oxo-2,3-dihydro-1H-indole-5-carboxylic Acid Methylamide

To a solution of 2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid (293 mg,1.65 mmol) in N₁N-dimethylformamide (15 mL) were added methylamine (2 Msolution in tetrahydrofuran, 0.91 mL, 1.82 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (698 mg,3.64 mmol), and 4-dimethylaminopyridine (882 mg, 7.28 mmol). Thereaction mixture was stirred at room temperature over night. The solventwas removed in vacuo, and the residue was dissolved in 5 mL of achloroform/methanol mixture (85:15). HCl in diethyl ether (3 M) wasadded until acidic pH. The solution was placed on ashort column ofsilica (glass sinter funnel d=70 mm, using chloroform/ethanol, 90:10, asthe eluent affording 195 mg (62% yield) of the pure product as a palepink solid: mp 295 IC (decomp.); MS (BID m/z (relative intensity) 190(66, M⁺), 160 (100), 132 (35), 104 (15), 77 (14).

Example 40 7-[3-(4-Methylpierazin-1-yl)propoxy]-3H-quinazolin-4-one

To a solution of 3-(4-methylpiperazin-1-yl)propan-1-ol (1.19 g, 7.52mmol; described in Brundage, Steck. J. Am. Chem. Soc., 1959, 81, 6511)in N,N-dimethylformamide (5 mL) was added sodium hydride (300 mg, 7.52mmol, 60% dispersion in oil), and the mixture was stirred at roomtemperature for 55 min. 7-fluoro-3H-quinazolin-4-one (411 mg, 2.51 mmol;described in Rewcastle G. et al J. Med. Chem., 1996, 39, 4, 918-928) wasadded in portions, and the mixture was heated at 140° C. for 1.5 h. Themixture was allowed to cool, and the solvent was removed in vacuo. Theresidue was partitioned between ethyl acetate and water at pH 7(adjusted by adding an aqueous hydrochloric acid solution, 2 M). Theaqueous layer was extracted with another portion of ethyl acetate. Tothe aqueous layer was added a saturated NaHCO₃ solution followed byextraction with tetrahydrofuran. The combined organic layers were dried(Na₂SO₄), and the solvent was removed in vacuo affording 0.55 g of ayellowish semi-solid which was used in the next step without furtherpurification.

Example 41 4-Chloro-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline

A mixture of crude7-[3-(4-methylpiperazin-1-yl)propoxy]-3H-quinazolin-4-one from Example40 and phosphorous oxychloride (3 mL) was heated at reflux for 30 min.N,N-Dimethylaniline (0.3 mL) was added whereby the solubility increased.The mixture was heated for another 30 min, and the excess of phosphorousoxychloride was removed in vacuo. The residue was partitioned betweenethyl acetate and a saturated NaHCO₃ solution. The organic layer wasdried (MgSO₄), and the solvent was removed in vacuo. The crude productwas purified on a silica column using chloroform/methanol, 85:15, as theeluent affording 69 mg (9% yield) of the title compound as a whitesolid: MS (ESP) m/z 321 (M⁺+1).

Example 42 4-Chloro-8-(2-morpholinylethoxy)quinazoline

To a solution of 4-chloroquinazolin-8-ol (203 mg, 1.12 mmol; describedin U.S. Pat. No. 5,270,466), triphenylphosphine (442 mg, 1.69 mmol), andN-(2-hydroxyethyl)morpholine (221 mg, 1.69 mmol) in anhydroustetrahydrofuran (5 mL) was added dropwise a solution of diethylazodicarboxylate (294 mg, 1.69 mmol) in tetrahydrofuran (3 mL). Thereaction mixture was stirred at ambient temperature for 45 nmin. Thesolvent was removed in vacuo, and the residue was purified by columnchromatography on silica using chloroform/ethanol, 95:5, as the eluentto give 280 g (85% yield) of the title compound as a orange oil: MS(ESP) m/z 294 (M++I).

Example 433-[7-(3-Morpholin-4-yl-propoxy)quinazolin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carboxylicAcid Dimethylamide

To a suspension of sodium hydride (20 mg, 0.495 mmol, 60% dispersion inoil) in N,N-dimethylformamide (2 mL) was added2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid dimethylamide (81 mg,0.396 mmol) under argon atmosphere. The mixture was stirred for 20 min,and then a solution of 4-chloro-7-(3-morpholin-4-ylpropoxy)quinazoline(61 mg, 0.198 mmol) in N,N-methylformamide (2.2 mL) was added dropwiseover 5 min. The obtained red solution was stirred at room temperaturefor 3 h. The solvent was removed in vacuo, and the mixture waspartitioned between ethyl acetate and water. A few drops of an aqueoushydrochloric acid solution (2 M) was added and the pH was adjusted to 8by the addition of an aqueous solution of saturated NaHCO₃. The productwas separated in a separator funnel, and filtered and washed with waterand diethyl ether. After drying in vacuo, 55 mg (60% yield) of the titlecompound was obtained as a yellow powder: mp 167.5-168.7° C.; MS (ESP)m/z 476 (M⁺+1).

Example 443-[7-(3-Morpholin-4-yl-propoxy)-quinazolin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carboxylicAcid Methylamide

To a suspension of sodium hydride (21 mg, 0.526 mmol, 60% dispersion inoil) in N,N-dimethylformamide (4 mL) was added2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methylamide (80 mg, 0.421mmol). 4-Chloro-7-(3-morpholin-4-ylpropoxy)quinazoline (65 mg, 0.210mmol; described in WO 97/42187) was added in portions after 25 min. Thedark red solution was stirred at room temperature over night. Thesolvent was removed in vacuo, and the residue was dissolved in a mixtureof methanol, ethyl acetate, and chloroform. The HCl-salt was prepared byadding HCl in diethyl ether (3 M) followed by evaporation of about 75%of the solvent volume. Ethyl acetate was added, and the precipitatedHCl-salt was filtered, washed with ethyl acetate, and dried. TheHCl-salt was dissolved in an aqueous 2 M NaOH solution and extracted twotimes with ethyl acetate. The pH was adjusted to 8 followed by threeextractions with ethyl acetate. The phases were combined and dried(Na₂SO₄). After filtration, the solvent was removed in vacuo affording40 mg (41% yield) of the title compound as a yellow solid: mp 195-198°C.; MS (ESP) m/z 462 (M⁺+1).

Example 453-{7-[3-(4-Methylpiperazin-1-yl)propoxy]quinazolin-4-yl]}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrileDihydrochloride

To a suspension of sodium hydride (22 mg, 0.538 mmol, 60% dispersion inoil) in N,N-dimethylformamide (1.5 mL) was added 5-cyanooxindole (68 mg,0.430 mmol). A dark yellow solution was obtained after 15 rain, and asolution of 4-chloro-7-[3-(4 methylpiperazin-1-yl)propoxy]quinazoline(69 mg, 0.215 mmol) in N,N-dimethylformamide (1.5 mL) was addeddropwise. A clear red solution was initially formed and by the end ofthe addition a precipitate was formed. The reaction mixture was stirredat room temperature for 2 h. The solvent was removed in vacuo, and theresidue was partitioned between ethyl acetate and an aqueoushydrochloric acid solution (2 M). The aqueous layer was washed withanother portion of ethyl acetate. The pH of the aqueous layer wasadjusted to 6 by adding a 2 M NaOH_((aq)) solution. After washing withethyl acetate, the aqueous layer was alkalized to pH 8 by addition of asaturated NaHCO_(3(aq)) solution followed by two extractions ofchloroform and one with tetrahydrofuran. The chloroform- andtetrahydrofuran layers were dried Na₂SO₄), combined, and the solvent wasremoved in vacuo. The residue was dissolved in a mixture of methanol,chloroform, and ethyl acetate. A solution of HCl in diethyl ether wasadded at 0° C. Half the volume was removed in vacuo, and ethyl acetatewas added. The precipitated HCl-salt was filtered and washed with ethylacetate. Drying in vacuo at 40° C. afforded 51 mg (43% yield) of thetitle compound as an orange solid: mp 200° C. (decomp.); MS (MSP) m/z443 (M⁺+1).

Example 462-Hydroxy-3-[8-(2-morpholin-4-ylethoxy)quinazolin-4-yl]-1H-indole-5-carbonitrileHydrochloride

To a solution of 5-cyanooxindole (226 mg, 1.43 mmol) inN,N-dimethylformamide (4 mL) was added sodium hydride (76 mg, 1.91 mmol,60% dispersion in oil). A solution of4-chloro-8-(2-morpholin-4-ylethoxy)quinazoline (0.28 g, 0.95 mmol) inN,N-dimethylformamide (3 mL) was added dropwise after 10 min. The colourchanged to red, and the mixture was stirred at room temperature for 30min. The solvent was removed in vacuo, and the residue was suspended inan aqueous hydrochloric acid solution (2 M) and ethyl acetate. Theheterogeneous aqueous layer was washed with another portion of ethylacetate. To the aqueous mixture was added NaHCO₃(s) until pH 8, followedby five extractions with chloroform. The combined chloroform layers weredried (Na₂SO₄), and the solvent was removed in vacuo affording 256 mg ofan orange crude product. Part of this material (61 mg) was dissolved ina 1:1 mixture of methanol and dichloromethane, and a solution of HCl indiethyl ether (3 M) was added dropwise at 0° C. until slightly acidic.About 60-75% of the solvent volume was removed in vacuo, and ethylacetate was added. The precipitated HCl-salt was filtered and washedwith ethyl acetate and dried in vacua affording 49 mg of the titlecompound as a red solid: MS (ESP) m/z 416 (M⁺+1).

Example 473-[7-(3-Morpholin-4-yl-propoxy)quinazolin-4-yl]-6-propyl-1H-indol-2-olHydrochloride

To a suspension of sodium hydride (30 mg, 0.756 mmol, 60% dispersion inoil) in N,N-dimethylformamide (2 mL) was added6-propyl-1,3-dihydro-indol-2-one (106 mg, 0.605 mmol). The mixture wasstirred at room temperature for 1 h, and a solution of4-chloro-7-(3-morpholin-4-ylpropoxy)quinazoline (93 mg, 0.302 mmol;described in WO 97/42187) in N,N-dimethylformamide (1.2 mL) was addeddropwise. The obtained red solution was stirred for 2 h. The solvent wasremoved in vacuo, and the residue was partitioned between an aqueoushydrochloric acid solution (2 M) and ethyl acetate. Some solid materialremained. The aqueous layer together with insoluble material was washedwith another portion of ethyl acetate. The aqueous mixture was aikalizedto pH 8 by adding an aqueous 45% NaOH solution and extracted with ethylacetate. The organic phase was dried (Na₂SO₄), and the solvent wasremoved in vacuo. The crude product was dissolved in ethyl acetate,isopropyl ether, and a few drops of ethanol. A solution of HCl indiethyl ether (3 M) was added at 0° C. The precipitated HCl-salt wasfiltered and washed with ethyl acetate affording 98 mg (62% yield) ofthe title compound as an orange powder: MS (ESP) m/z 447 (M⁺+1).

Example 48 6-Bromo-5-(2-chloroacetyl)1,3-dihydroindol-2-one

6-Bromooxindole (500 mg, 2.4 mmol) was added to aluminum trichloride(1.08 g, 8.1 mmol) in dichloroethane (1.5 mL). Chloroacetylchloride wasslowly added under gas evolution and the mixture was heated at 50° C.for 18 h. The reaction was cooled to room temperature and poured intoice water. The precipitate was collected and purified by flash silicagel chromatography using chloroform/methanol (50:1->20:1->10:1->5:1) asthe eluent to give 429 mg (63% yield) the title compound as a whitepowder: mp 238-239° C.;

ESMS m/z 289.92 (M⁺+1).

Example 49 6-Bromo-2-oxo-2,3-dihydro-1H-indole-5-carboxylic Acid

6-Bromo-5-(2-chloroacetyl) 1,3-dihydroindol-2-one (422 mg, 1.46 mmol) inpyridine (5 mL) was heated at 70° C. for 3.5 h. The mixture was allowedto cool, the precipitate was filtered and washed with ethanol. The solidwas dissolved in 2 M NaOH_((aq)) (8 mL) and heated to 70° C. for 1 h and20 min, cooled on an ice bath and acidified with conc. HCl_((aq)) to pH2. The brown precipitate was collected by filtration. This, andadditional precipitate which was formed in the motherliquor over night,was dried in vacuo at 35° C. to give 315 mg (84% yield) of the titlecompound as a brown powder: mp 294° C. (decomp.); MS (TSP) m/z 257(M⁺+1).:

Example 50 6-Bromo-2-oxo-2,3-dihydro-1H-indole-5-carboxylic AcidMethylamide

6-Bromo-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid (510 mg, 2.0 mmol)was dissolved in N,N-dimethylformamide (20 MTL) and methylamine intetrahydrofuran (2 M, 1095 μL),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (840 mg, 4.4mmol) and dimethylaminopyridin (1.062 g, 8.8 mmol) were addedsequentially and the mixture was stirred at room temperature for 19 h.The mixture was acidified with an aqueous hydrochloric acid solution (1M), concentrated and co-evaporated with toluene three times. The residuewas dissolved in an aqueous hydrochloric acid solution (1 M), NaCl (s)was added and the solution was extracted several times withtetrahydrofuran. The organic phase was washed with an aqueoushydrochloric acid solution (1 M) and the combined aqueous phases werewashed with tetrahydrofuran. The combined tetrahydrofuran phases weredried (MgSO₄), filtered and concentrated in vacuo. The crude product waspurified by flash silica gel chromatography using ethylacetate/methanol/water (15:1:0->10:1:0->5:1:0->2:1:0->7:2:1). Thefractions containing the product were concentrated, dissolved inmethanol and filtered to remove silica gel. After evaporation of thesolvent, the residue was crystallized from methanol to give 137 mg (26%yield) of the title compound as a pink solid: mp 279° C. (decomp.); ESMSm/z 271.0 (M⁺+1).

Example 516-Bromo-3-[7-(3-morpholin-4-yl-propoxy)quinazolin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carboxylicAcid Methylamide

6-Bromo-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methylamilde (73mg, 271 μmol) in N,N-dimethylformamide (3 mL) was added to sodiumhydride (12.9 mg, 323 μmol, pre-washed with hexane). After stirring for10 min, 4-chloro-7-(3-morpholin-4-ylpropoxy)quinazoline (39.8 mg, 123mmol; described in WO 97/42187) was added. The reaction was stirred atroom temperature for 2.5 h, concentrated and co-evaporated with toluenethree times. The residue was dissolved in 10% NaOH_((aq)) and extractedwith ethyl acetate and the organic phases were washed with 10%NaOH_((aq)). The combined aqueous phases were acidified with 1 M HCl topH 2 and extracted with ethyl acetate. Using a 10% aqueous solution ofNaOH and NaHCO₃ (s) the pH of the aqueous phase was adjusted to 8.5 andextracted with tetrahydrofuran. The organic phase was dried (MgSO₄),filtered and concentrated in vacuo. The residue was dissolved inmethanol and HCl in diethyl ether (1 M, 3 mL) was added. Thehydrochloride salt was precipitated by the addition of diethyl ether,filtered and washed with diethyl ether. After drying in vacuo at 35° C.the crude product was purified by preparative HPLC (X-Terra C8 column,19×300 mm), using a gradient of A (water 95%, containing NH₄OAc (0.01M), and 5% acetonitrile) and B (acetonitrile), going from 0% to 100% Bover a period of 22 min. The fractions were collected and concentratedin vacuo to give 21 mg (30% yield) of the title compound as a yellowserni-sblid: ESMS m/z 542.3 (M⁺+1).

Example 52 2-(4-Ethylphenyl)-N-methoxyacetamide

(4-Ethylphenyl)acetyl chloride (2.9 g, 16 mmol; described in Shah, S. etal. J. Med. Chem., 1992, 35, 3745-3754) was added to a vigorouslystirred solution of methoxyamine hydrochloride (1.5 g, 17.6 mmol) andsodium carbonate (3.4 g, 32 mmol) in a mixture of toluene (15 mL) andwater (15 mL). The reaction mixture was stirred for 4 h at roomtemperature and then extracted with ethyl acetate (3×30 mL). Thecombined extracts were washed with brine (30 mL), dried (MgSO₄), and thesolvent was removed in vacuo and dried at 25° C. in vacuo over night toafford 2.7 g. The residue was purified on a silica gel column usingethyl acetate as the eluent to afford 2.4 g (77% yield) of titlecompound as a colorless oil: MS (TSP) m/z 194 (M⁺+1).

Example 53 6-Ethyl-1-methoxy-1,3-dihydroindol-2-one

To a solution of 2-(4-ethylphenryl)-N-methoxyacetamide (2.4 g, 12.4mmol) in methylene chloride (35 mL), cooled on an ice-bath, was addedtert-butyl hypochlorite. (1.7 mL, 14.9 mmol). The ice-bath was removedand the solution was allowed to reach room temperature. After 1.5 hreaction time, the solvent was removed in vacuo. The residue wasdissolved in nitromethane (3 mL) and added to nitromethane (100 mL)containing zinc acetate (11.4 g, 62 mmol) at 95° C. After 30 min,insoluble materials were filtered off, washed with ethyl acetate, andthe combined solvents were removed in vacuo. The residue was dissolvedin ethyl acetate (200 mL) and washed with 5% aqueous solution of NaHCO₃(150 nL), brine (50 mL), dried (MgSO₄), and concentrated to afford 2.2 gof a crude residue. The residue was purified on a silica gel columnusing diethyl ether as the eluent to afford 1.8 g (76% yield) of titlecompound as a brownish oil: MS (TSP) m/z 192 (M⁺+1).

Example 54 6-Ethyl-1,3-dihydroindol-2-one

6-Ethyl-1-methoxy-1,3-dihydroindol-2-one (0.5 g, 2.6 mmol) was dissolvedin methanol (15 mL), palladium (10%) on charcoal (0.3 g) was added andthe mixture was hydrogenated at atmospheric pressure and roomtemperature. After 3 h the mixture was filtered through silica to removethe catalyst and the solvent was evaporated in vacuo. The residue wasdried at 25° C. in vacua over night to afford 0.27 g (64% yield) oftitle compound as a white solid: MS (TSP) m/z 162 (M⁺+1).

Example 556-Ethyl-3-[7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]-1H-indol-2-olhydrochloride

A mixture of sodium hydride (31 mg, 0.78 mmol, pre-washed with hexane)in N,N-dimethylformamide (1 mL) was added to6-ethyl-1,3-dihydroindol-2-one (100 mg, 0.62 mmol) inN,N-dimethylformamide (2 mL). The formed yellow mixture was stirred atroom temperature for 5 min and4-chloro-7-(3-morpholin-4-yl-propoxy)quinazoline (95 mg, 0.31 mmol;described in: WO 97/42187) in N,N-dimethylformamide (1 mL) was added.The obtained red solution was stirred for 1 h and the solvent wasremoved in vacuo. The residue was partitioned between an aqueoussolution of hydrochloric acid (2 M) and ethyl acetate. Some solidmaterial remained and the aqueous layer together with the insolublematerial was washed with another portion of ethyl acetate. The aqueousmixture was alkalized to pH 10 by adding 2 M NaOH_((aq)), and extractedwith ethyl acetate (3×5 mL). The combined organic layers were dried(Na₂SO₄), and the solvent was removed in vacuo and dried at 25° C. invacuo over night to afford 80 mg. The residue was purified on a silicagel column using chloroform/methanol, 23:2, as an eluent. Fractionscontaining the product were collected and evaporated in vacuo and driedat 25° C. in vacuo over night. The residue was dissolved in diethylether and treated with HCl in diethyl ether (5 M). The hydrochloride wasdried at 25° C. in vacuo over night to afford 30 mg (19% yield) of titlecompound as an orange powder: MS (ESP) m/z 433 (M⁺+1).

Example 56 N-Methoxy-2-(4-Rropvlphenyl)acetamide

The reaction was performed as described in Example 52 using(4-propylphenyl)acetic acid (described in Kindler, et al Chem Ber.,1943, 76, 308) that was converted to the acid chloride using thionylchloride to afford 5.8 g (58% yield) of title compound as a colorlessoil: MS (TSP) m/z 208 (M⁺+1).

Example 57 1-Methoxy-6-propyl-1,3-dihydroindol-2-one

The reaction was performed as described in Example 53 usingN-methoxy-2-(4-propyl-phenyl)acetamide to afford 4.4 g (76% yield) oftitle compound as a brownish oil: MS (TSP) m/z 206 (M⁺+1).

Example 58 6-Propyl-1,3-dihydroindol-2-one

1-Methoxy-6-propyl-1,3-dihydroindol-2-one (1.54 g, 7.5 mmol) wasdissolved in methanol (10 mL), palladium (10%) on charcoal (0.7 g) wasadded and the mixture was hydrogenated at 3.5 kg pressure and at roomtemperature. After 20 h the mixture was filtered through silica toremove the catalyst and the solvent was evaporated in vacuo to afford1.18 g (90% yield) of title compound: MS (TSP) m/z 176 (100, M⁺+1).

Example 596-Methyl-3-[7-(3-morpholin-4-yl-prolpoxy)-quinazolin-4-yl]-1H-indol-2-ol

The reaction was performed as described in Example 55 using6-methyl-1,3-dihydroindol-2-one (described in Kawase M. et al J. Org.Chem.,. 1989, 54, 3394-3403) and4-chloro-7-(3-morpholinyl-propoxy)quinazoline (described in: WO97/42187). The crude product was purified by preparative HPLC (X-TerraC8 column, 19×300 mm), using a gradient of water/acetonitrile, 70/30, towater/acetonitrile, 30/70, to afford 8 mg (6% yield) of title compoundas a orange solid: MS (ESP) m/z 419 (M⁺+1).

Example 60 5-Bromo-6-methyl-1,3-dihydroindol-2-one

6-Methyl-1,3-dihydro-2H-indol-2-one (0.107 g, 0.73 mmol) was dissolvedin acetonitrile (3 mL) and stirred for 5 min at 0° C. N-Bromosuccinimide(0.129 g, 0.73 mmol) was added and the resulting reaction mixture wasstirred for 4 h at 0° C. The reaction mixture was poured onto water andthe resulting crystals were collected by vacuum filtration, followed bydrying over night in a vacuum desiccator over MgSO₄/CaSO₄ to afford0.091 g (55% yield) of the title compound as a reddish-brown solid: ¹HNMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 7.41 (s, 1H), 6.82 (s, 1H), 3.49(s, 2H), 2.34 (s, 3H).

Example 61 6-Bromo-5-nitro-1,3-dihydroindol-2-one

6-Bromo-1,3-dihydro-2H-indol-2-one (0.500 g, 2.36 mmol) was dissolved inconc. sulfuric acid (6 mL) and stirred for 10 min at room temperatureand solid potassium nitrate (0.238 g, 2.36 mmol) was added in twoportions. The resulting reaction mixture was stirred over night at roomtemperature. The mixture was poured onto ice-water and the reddish-brownprecipitates were collected by vacuum filtration and dried over night ata vacuum desiccator over MgSO₄/CaSO₄ to afford 0.535 g (88% yield) ofthe title compound: ¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 8.01 (s,1H), 7.20 (s, 1H), 3.62 (s, 2H).

Example 625-Bromo-6-methyl-3-[7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]-1H-indol-2-oldihydrochloride

To a N,N-dimethylformamide (1.3 mL) suspension of sodium hydride (0.011mg, 0.44 mmol, 60% in oil, pre-washed with hexane) was added5-bromo-6-methyl-1,3-dihydroindol-2-one (0.079 g, 0.35 mmol). The formedred mixture was stirred for 10 min at room temperature and4-chloro-7-(3-morpholin-4-ylpropoxy)quinazoline (0.055 g, 0.18 mmol;described in WO97/42187) was added. The resulting reaction mixture wasstirred for 2 h and then the solvent was removed in vacuo. The residuewas purified on a silica gel column using dichloromethane/methanol,10:1, as an eluent to afford, after drying, 0.036 g (40% yield) of thetitle compound as the free base (yellow solid). This residue (0.026 g,0.05 mmol) was dissolved in dichloromethane/methanol, 1:1, and treatedwith 1 M HCl in diethyl ether at 0° C. The resulting orange solids werecollected by vacuum filtration and washed with diethyl ether to afford0.016 g of the tide compound: MS (CI) m/z 498 (M⁺+1).

Example 636-Bromo-3-[7-(3-morpholin-4-yliropoxy)quinazolinyvll-5-nitro-1H-indol-2-oldihydrochworide

Sodium hydride (0.013 mg, 0.5 mmol, 60% in oil, pre-washed with hexane)was suspended in N,N-dimethylformamide (2.0 mL) and to this stirredmixture, 6-bromo-5-nitro-1,3-dihydroindol-2-one (0.103 g, 0.4 mmol) wasadded. The formed red mixture was stirred for 10 min at room temperatureand 4-chloro-7-(3-morpholin-4-ylpropoxy)quinazoline (0.062 g, 0.2 mmol;described in WO97/42187) was added. The resulting reaction mixture wasstirred for 2 h and the solvent was removed in vacuo. The residue waspurified on a silica gel column using dichloromethane methanol, 15:1, aseluent to afford, after drying, 0.039 g (37% yield) of the titlecompound as the free base. (yellow solid). This residue (0.03 g, 0.057mmol) was dissolved in dichloromethane/methanol, 1:1, and treated with 1M HCl in diethyl ether at 0° C. The resulting orange crystals werecollected by vacuum filtration and washed with diethyl ether to afford0.028 g (81% yield) of the title compound: MS (CI) m/z 529 (M⁺+1).

Example 64 7-(3-Dimethylaminoprolpoxy)-3H-quinazolin-4-one

3-Dimethylaminopropan-1-ol (0.95 mL, 8.0 mmol) was dissolved inN,N-dimethylformamide (5 mL) under N₂ atmosphere and stirred for 10 minat 0° C. To this solution, sodium hydride (60% dispersion in oil, 0.35g, 8.8 mmol) was added and the resulting reaction mixture was allowed towarm up to room temperature and stirred for 1 h. A solution of7-fluoro-3H-quinazolin 4-one (328 mg, 2 mmol; described in Rewcastle G.et al J. Med Chem., 1996, 39, 4, 918-928) in N,N-dimethylformamide (5mL) was added and the mixture was stirred for 2 h at 140° C. Thereaction mixture was cooled down to room temperature and diluted withaqueous saturated NaHCO₃ solution followed by extraction with ethylacetate (3×50 mL). The combined organic layer was dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residual oil was re-concentratedwith toluene and the semisolid product crystallised upon treatment withdiethyl ether. The crystals were collected by vacuum filtration anddried in a desiccator to give 0.41 g (83% yield) of the title compoundas a solid: ¹H NMR (DMSO-d6, 300 MHz) δ 12.00 (br s, 1H), 8.04 (s, 1H),8.01 (dd, J=8 and 2 Hz, 1H), 7.09 (d, J=3 Hz, 1H), 7.06 (s, 1H), 4.13(t, J=6 Hz, 2H), 2.36 (t, J=7 Hz, 2H), 2.14 (s, 6H), 1.88 (m, 2H).

Example 65 7-(2-Dimethylaminoethoxy)-3H-quinazolin-4-one

The compound was prepared as described in Example 64 using2-dimethylaminoethanol (1.5 mL, 15 mmol) and7-fluoro-3H-quinazolin-4-one (0.492 g, 3 mmol) affording 0.52 g (75%yield) of the title compound as a solid: MS (ES) nvz 234 (M⁺+1).

Example 66 7-[2-(Isopropylmethylamlno)ethoxy]-3H-quinazolin-4-one

The compound was prepared as described in Example 64 using2-(isopropylmethylamino)ethanol (1.168 g, 10.0 mmol) and7-fluoro-3H-quinazolin-4-one (0.41 g, 2.5 mmol) to give 0.512 g (78%yield) of the title compound as a solid. MS (ES) m/z 262 (M⁺+1).

Example 67 7-(2-Diisopropylaminoethoxy)-3H-quinazolin-4-one

The compound was prepared as described in Example 64 using2-(diisopropylamino)ethanol (1.59 mL, 9.0 mmol) and7-fluoro-3H-quinazolin-4-one (0.492 g, 3.0 mmol) to give 0.66 g (76%yield) of the tide compound as white fluffy crystals: ¹H NMR (DMSO-d6,300 MHz) δ 12.07 (br s, 1H), 8.04 (s, 1H), 8.01 (dd, J=6 and 4 Hz, 1H),7.07 (d, J=4 Hz, 1H), 7.05 (s, 1H), 4.01 (t, J=7 Hz, 2H), 3.01 (m, 2H),2.80 (t, J=7 Hz, 2H), 0.99 (d, J=7 Hz, 12H).

Example 68 7-(3-(4-Chloroquinazolin-7-yloxy)propyl]dimethylamine

7-(3-Dimethylaminopropoxy)-3H-quinazolin-4-one (0.2 g, 0.21 mmol) wasadded to stirred phosphorus oxychloride (5 mL). The vessel was closedand the mixture was heated to 110° C. and kept stirring for 2 h. Theexcess of the phosphorus oxychloride was removed in vacuo and theresidue was dissolved in a water/chloroform mixture. The aqueous layerwas analyzed with an aqueous saturated NaHCO₃ solution and the organiclayer was separated. The water layer was extracted two times withchloroform and the combined organic layer was washed with brine driedover anhydrous Na₂SO₄ and concentrated in vacuo. The material was usedin the next step without further purification.

Example 69 [2-(4-Chloroquinazolin-7-yloxy)ethyl]dimethylamine

The compound was prepared as described in Example 68 using7-(3-dimethylaminoethoxy)-3H-quinazolin-4-one (0.270 g, 1.16 mmol). Thematerial was used in the next step without further purification.

Example 70 [2-(4-Chloroquinazolin-7-yloxy)ethyl]isopopylmethylamine

The compound was prepared as described in Example 68 using7-[2-(isopropylmethylamino)ethoxy]-3H-quinazolin-4-one (0.300 g, 1.15mmol). The material was used in the next step without furtherpurification.

Example 71 [2-(4-Chloro-quinazolin-7-yloxy)ethyl]diisopronylamine

The compound was prepared as described in Example 68 using7-(2-diisopropylaminoethoxy)-3H-quinazolin-4-one (0.330 g, 1.14 mmol).The material was used in the next step without further purification.

Example 723-[7-(3-Dimethylaminopropoxy)quinazolin-4-yl]-2-hydoxy-1H-indol-5-carbonitrilehydrochloride

To an ice-bath cooled solution of 5-cyano-1,3-dihydroindol-2-one (0.255g, 1.62 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride(60% dispersion in oil, 0.078 g, 1.94 mmol) and the ice-bath wasremoved. After 15 min stirring, the ice-bath cooling was resumed and asolution of [3-(4-chloroquinazolin-7-yloxy)propyl]dimethylamine (0.265g, 0.81 mmol) in N,N-dimethylformamide (6 mL) was slowly added. Thereaction mixture was stirred for 12 h and quenched with aqueoussaturated NaHCO₃ solution followed by extraction with ethyl acetate(3×100 mL). The combined organic extracts were dried over anhydrousNa₂SO₄ and concentrated in vacuo affording the free base as a yellowsolid. The residue was dissolved in chloroform/ethanol, 1:1, and treatedwith 1 M HCl in diethyl ether at 0° C. The resulting solid werecollected by vacuum filtration and washed with diethyl ether to obtain0.14 g (41% yield) of the title compound as a solid: ¹H NMR (DMSO-d6,300 MHz) δ 11.02 (br s, 1H), 10.42 (br s, 1H), 8.72 (br s, 1H), 8.49 (s,1H), 8.15 (s, 1H), 7.44 (dd, J=8 and 1 Hz, 1H), 7.22 (d, J=9 Hz, 1H),7.11 (s, 1H), 7.01 (d, J=8 Hz, 1H), 4.29 (t, J=6 Hz, 2H), 3.25 (m, 2H),2.80 (s, 6H), 2.24 (m, 2H).

Example 733-[7-(2-Dimethylaminoethoxy)quinazolin-4-yl]-2-hydoxy-1H-indol-5-cabonitrilefumarate

The compound was prepared as described in Example 72 using[2-(4-chloroquinazolin-7-yloxy)-ethyl]dimethylamine (1.15 mmol) andfumaric acid to give 0.22 g (40% yield) of the title compound as asolid. ¹H NMR (DMSO-d6, 300 MHz) δ 10.85 (br s, 1H), 8.81 (br s, 1H),8.47 (s, 1H), 8.20 (b s, 1H), 7.38 (d, J=8 Hz, 1H), 7.18 (d, J=6 Hz,1H), 7.07 (s, 1H), 6.97 (d, J=8 Hz, 1H), 6.58 (s, 1H), 4.30 (t, J=5 Hz,2H), 2.87 (t, J=5 Hz, 2H), 2.37 (s, 6H).

Example 743-{7-[2-(Isopropylmethylamino)ethoxy]quinazolin-4-yl}-2-oxo-2,3-dihydro-1H-indol-5-carbonitrileFumarate

The compound was prepared as described in Example 72 using[2-(4-chloroquinazolin-7-yloxy)ethyl]-isopropylmethylamine (1.15 mmol)and fumaric acid to give 0.185 g (32% yield) of the title compound as asolid: ¹H NMR (DMSO-d6, 300 MHz) δ 10.84 (br s, 1H), 8.80 (br s, 1H),8.46 (s, 1H), 8.19 (br s, 1H), 7.37 (d, J=8 Hz, 1H), 7.17 (d, J=9 Hz,1H), 7.06 (s, 1H), 6.95 (d, J=8 Hz, 1H), 6.56 (s, 1H), 4.29 (t, J=5 Hz,2H), 3.08 (t, J=7 Hz, 1H), 3.00 (t, J=6 Hz, 2H), 2.40 (s, 3H), 1.06 (d,J=6 Hz, 6H).

Example 753-[7-(2-Diisopronylamino)ethoxy)quinazolin-4-yl]-2-hydroxy-1H-indol-5-carbonitrilefumarate

The compound was prepared as described in Example 72 using[2-(4-chloroquinazolin-7-yloxy)-ethyl]diisopropylamine (1.14 mmol) andfumaric acid to give 0.20 g (35% yield) of the title compound as asolid: ¹H NMR (DMSO-d₆, 300 MHz) δ 11.00 (b s, 1H), 8.84 (br s, 1H),8.57 (s, 1H), 8.29 (br s, 1H), 7.50 (d, J=8 Hz, 1H), 7.29 (d, J=9 Hz,1H), 7.15 (s, 1H), 7.08 (d, J=8 Hz, 1H), 6.70 (s, 1H), 4.26 (br s, 2H),3.29 (t, J=6 Hz, 2H), 3.10 (br s, 2H), 1.19 (d, J=6 Hz, 6H), 1.16 (d,J=7 Hz, 6H).

Pharmaceutical Composition

According to one aspect of the present invention there is provided apharmaceutical composition comprising a compound of the presentinvention, as hereinbefore defined, for use in prevention and/ortreatment of dementia related diseases, Alzheimer's Disease andconditions associated with glycogen synthase kinase-3 and otherconditions listed below.

The composition may be in a form suitable for oral administration, forexample as a tablet, pill, syrup, powder, granule or capsule, forparenteral injection (including intravenous, subcutaneous,intramuscular, intravascular or infusion)as a sterile solution,suspension or emulsion, for topical administration e.g. as an ointment,patch or cream or for rectal administration e.g. as a suppository.

In general the above compositions may be prepared in a conventionalmanner using pharmaceutically acceptable carriers or diluents.

Suitable daily doses of the compounds of formula I in the treatment of amammal, including man, are approximately 0.01 to 250 mg/kg bodyweight atperoral administration and about 0.001 to 250 mg/kg bodyweight atparenteral administration. The typical daily dose of the activeingredients varies within a wide range and will depend on variousfactors such as the relevant indication, severity of the illnesstreated, the specific compound used, the route of administration, theage, weight and sex of the patient and may be determined by a physician.

Illustrate representative pharmaceutical dosage forms containing acompound of formula I, as a free base or a pharmaceutically acceptablesalt thereof, are described in WO 97/42187.

Medical Use

Surprisingly, it has been found that the compounds defined in thepresent invention, as hereinbefore defined, are useful in therapy. Thecompounds of the present invention are well suited for inhibitingglycogen synthase kinase-3 (GSK3). Accordingly, the compounds of thepresent invention are expected to be useful in the prevention and/ortreatment of conditions associated with glycogen synthase kinase-3activity, i.e. the compounds may be used to produce an inhibitory effectof GSK3 in mammals, including man, in need of such prevention and/ortreatment. GSK3 is highly expressed in the central and peripheralnervous system and in other tissues. Thus, it is expected that compoundsof the invention are well suited for the prevention and/or treatment ofconditions associated with glycogen synthase kinase-3 in the central andperipheral nervous system. In particular, the compounds of the inventionare expected to be suitable suitable in the manufacture of a medicamentfor the prevention and/or treatment of dementia related diseases andAlzheimer's Disease.

The dementia related diseases are selected from the group consisting ofFrontotemporal dementia Parkinson's Type, Parkinson dementia complex ofGuam, HIV dementia, diseases with associated neurofibrillar tanglepathologies, predemented states, vascular dementia, dementia with Lewybodies, Frontotemporal dementia and dementia pugilistica.

The compounds of the invention are also expected to be suitable in themanufacture of a medicament for the prevention and/or treatment ofamyotrophic lateral sclerosis, corticobasal degeneration, Down syndrome,Huntington's Disease, Parkinson's Disease, postencephelaticparkinsonism, progressive supranuclear palsy, Pick's Disease,Niemann-Pick's Disease, stroke, head trauma and other chronicneurodegenerative diseases, Bipolar Disease, affective disorders,depression, schizophrenia, cognitive disorders, hair loss andcontraceptive medication.

The compounds of the invention are further expected to be suitable inthe manufacture of a medicament for the prevention and/or treatment ofMild Cognitive Impairment, Age-Associated Memory Impairment, Age-RelatedCognitive Decline, Cognitive Impairment No Dementia, mild cognitivedecline, mild neurocognitive decline, Late-Life Forgetfulness, memoryimpairment and cognitive impairment and androgenetic alopecia.

The invention also provides for a method of prevention and/or treatmentof dementia related diseases, Alzheimer's Disease and conditionsassociated with glycogen synthase kinase-3 and other conditions listedabove comprising administrering to a mammal, including man, in need ofsuch prevention and/or treatment a therapeutically effective amount ofcompounds of the present invention, as hereinbefore defined.

The present invention relates also to the use of a compound of thepresent invention as defined hereinbefore, in the manufacture of amedicament for the prevention and/or treatment of conditions associatedwith glycogen synthase kinase-3. In the context of the presentspecification, the term “therapy” includes treatment as well asprevention, unless there are specific indications to the contrary. Theterms “therapeutic” and “therapeutically” should be construedaccordingly.

Non-Medical Use

In addition to their use in therapeutic medicine, the compounds of thepresent invention as a free base or salts thereof, are also useful aspharmacological tools in the development and standardisation of in vitroand in vivo test systerns for the evaluation of the effects ofinhibitors of GSK3 related activity in laboratory animals such as cats,dogs, rabbits, monkeys, rats and mice, as part of the search for newtherapeutics agents.

Pharmacology

Determination of ATP competition in Scintillation Proximity GSK3β Assay.

GSK3β Scintillation Proximity Assay.

The competition experiments were carried out in duplicate with 10different concentrations of the inhibitors in clear-bottom microtiterplates (Wallac, Finland). A biotinylated peptide substrate,Biotin-Ala-Ala-Glu-Glu-Leu-Asp-Ser-Arg-Ala-Gly-Ser(PO₃H₂)-Pro-Gln-Leu(AstraZeneca, Lund), was added at a final concentration of 1 μM in anassay buffer containing 1 mU recombinant human GSK3, (Dundee University,UK), 12 mM morpholinepropanesulfonic acid (MOPS), pH 7.0, 0.3 mM EDTA,0.01% β-mercaptorethanol, 0.004% Brij 35 (a natural detergent), 0.5%glycerol and 0:5 μg BSA/25 μl: The reaction was initiated by theaddition of 0.04 μCi [γ-³³P]ATP (Amersham, UK) and unlabelled ATP at afinal concentration of 1 μM and assay volume of 25 μl. After incubationfor 20 min at room temperature, each reaction was terminated by theaddition of 25 μl stop solution containing 5 mM EDTA, 50 μM ATP, 0.1%Triton X-100 and 0.25 mg streptavidin coated Scintillation ProximityAssay (SPA) beads (Amersham, UK). After 6 hours the radioactivity wasdetermined in a liquid scintillation counter (1450 MicrbBeta Trilux,Wallac). The inhibition curves were analysed by non-linear regressionusing GraphPad Prism, USA. The K_(m) value of ATP for GSKjp, used tocalculate the inhibition constants (K_(i)) of the various compounds, was20 μM.

The following abbreviations have been used:

-   ATP Adenosine Triphophatase-   BSA Bovin Serum Albumin-   EDTA Ethylenediaminetetraacetic acid-   GSK3 Glycogen synthase kinase 3-   MOPS Morpholinepropanesulfonic acid-   SPA Scintillation Proximity Assay    Results

Typical K_(i) values for the compounds of the present invention are inthe range of about 0.001 to about 10,000 nM. Other values for K_(i) arein the range of about 0.001 to about 1000 nM. Further values for Ki arein the range of about 0.001 nM to about 300 nM.

1. A method for the prevention and/or treatment of dementia-relateddiseases, Alzheimer's Disease and conditions associated with glycogensynthase kinase-3, comprising administering to a patient in need of suchprevention and/or treatment a therapeutically effective amount of acompound of formula I

as a free base or a pharmaceutically acceptable salt thereof, wherein:R¹ is hydrogen or C₁₋₃alkyl; R² is hydroxy, halogeno, trifluoromethyl,cyano, amino, nitro, carboxy, C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkanoyloxy,C₂₋₄alkanoyl, C₁₋₄alkanoylamino, C₁₋₄alkoxycarbonyl, C₁₋₄alkylthio,C₁₋₄alkylsulphinyl, C₁₋₄alkylsulphonyl, carbamoyl, N-C₁₋₄alkylcarbamoyl,N,N-di(C₁₋₄alkyl)carbamoyl, aminosulphonyl, N-C₁₋₄alkylaminosulphonyl,N,N-di(C₁₋₄alkyl)aminosulphonyl, C₁₋₄alkylsulphonylamino, or a groupR⁴X¹, wherein X¹ is a direct bond, C₂₋₄alkanoyl, CONR⁵R⁶, SO₂NR⁷R⁸ orSO₂R⁹ (wherein R⁵ and R⁷ each independently are hydrogen or C₁₋₂alkyl,and R⁶, R⁸ and R⁹ each independently are C₁₋₄alkyl, and wherein R⁴ islinked to R⁶, R⁸ or R⁹); and R⁴ is phenyl or a 5 or 6 memberedheterocyclic group with one or two heteroatoms, selected independentlyfrom O, S and N, which heterocyclic group may be saturated orunsaturated and which phenyl or heterocyclic group may be substitutedwith one or two substituents selected independently from hydroxy,halogeno, C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkanoyloxy, trifluoromethyl,cyano, amino, nitro and C₁₋₄alkoxycarbonyl; R³ is hydroxy, halogeno,nitro, trifluoromethyl, C₁₋₃alkyl, cyano, amino or R¹⁰X², wherein X² isO, CH₂, S, SO, SO₂, NR¹¹CO, CONR¹², SO₂NR¹³, NR¹⁴ SO₂ or NR¹⁵ (whereinR¹¹, R¹², R¹³, R¹⁴ and R¹⁵ each independently are hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl), or X² is a direct bond; and R¹⁰ is selected fromone of the following groups: 1) hydrogen or C₁₋₅alkyl which may besubstituted with one or more groups selected independently from hydroxy,fluoro and amino; 2) C₁₋₅alkylX³COR¹⁶ (wherein X³ is O or NR¹⁷ (whereinR¹⁷ is hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹⁶ is C₁₋₃alkyl,NR¹⁸R¹ or OR²⁰ (wherein R¹⁸, R¹⁹ and R²⁰ each independently arehydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); 3) C₁₋₅alkylX⁴R²¹ (whereinX⁴ is O, S, SO, SO₂, OCO, NR²²CO, CONR²³, SO₂NR²¹, NR²⁵ SO₂ or NR²⁶(wherein R²², R²³, R²⁴, R²⁵ and R²⁶ each independently are hydrogen,C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²¹ is hydrogen, C₁₋₃alkyl,cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclicgroup with one or two heteroatoms selected independently from O, S andN, which C₁₋₃alkyl group may be substituted with one or two substituentsselected independently from oxo, hydroxy, halogeno and C₁₋₄alkoxy andwhich heterocyclic group may be substituted with one or two substituentsselected independently from oxo, hydroxy, halogeno, C₁₋₄alkyl,C₁₋₄hydroxyalkyl and C₁₋₄alkoxy); 4) C₁₋₅alkylX⁵C₁₋₅alkylX⁶R²⁷ (whereinX⁵ and X⁶ each independently are O, S, SO, SO₂, NR²⁸ CO, CONR²⁹, SO₂NR³⁰NR³¹ SO₂ or NR³² (wherein R²⁸, R²⁹, R³⁰R³¹ and R³² each independentlyare hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²⁷ is hydrogen orC₁₋₃alkyl); 5) C₁₋₅alkylR³³ (wherein R³³ is a 5 or 6 membered saturatedheterocyclic group with one or two heteroatoms selected independentlyfrom O, S and N, which heterocyclic group may be substituted with one ortwo substituents selected independently from oxo, hydroxy, halogeno,C₁₋₄alkyl, C₁₋₆carbonyl, C₁₋₄hydroxyalkyl and C₁₋₄alkoxy); 6)C₂₋₅alkenylR³³ (wherein R³³ is as defined hereinbefore); 7)C₂₋₅alkynylR³³ (wherein R³³ is as defined hereinbefore); 8) R³⁴ (whereinR³⁴ is a pyridone group, a phenyl group or a 5 or 6 membered aromaticheterocyclic group with 1 to 3 heteroatoms selected independently fromO, N and S, which pyridone, phenyl or heterocyclic group may carry up to5 substituents selected independently from hydroxy, halogeno, amino,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,C₁₋₄hydroxyalkoxy, carboxy, cyano, CONR³⁵R³⁶ and NR³⁷ CR³⁸ (wherein R³⁵,R³⁶, R³⁷ and R³⁸ each independently are hydrogen, C₁₋₄alkyl orC₁₋₃alkoxyC₂₋₃alkyl)); 9) C₁₋₅alkylR³⁴ (wherein R³⁴ is as definedhereinbefore); 10) C₂₋₅alkenylR³⁴ (wherein R³⁴ is as definedhereinbefore); 11) C₂₋₅alkynylR³⁴ (wherein R³⁴ is as definedhereinbefore); 12) C₁₋₅alkylX⁷R³⁴ (wherein X⁷ is O, S, SO, SO₂, NR³⁹CO,CONR⁴⁰, SO₂NR⁴¹, NR⁴² SO₂ or NR⁴ (wherein R⁴³, R³⁹, R⁴⁰, R⁴² and R⁴¹each -independently are hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR³⁴ is as defined hereinbefore); 13) C₂₋₅alkenylX⁸R³⁴ (wherein X⁸ is O,S, SO, SO₂, NR⁴⁴CO, CONR⁴⁵, SO₂NR⁴⁶, NR⁴⁷SO₂ or NR⁴⁸ (wherein R⁴⁴, R⁴⁵,R⁴⁶, R⁴⁷ and R⁴⁸ each independently are hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R³⁴ is as defined hereinbefore); 14)C₂₋₅alkynylX⁹R³⁴ (wherein X⁹ is O, S, SO, SO₂, NR⁴⁹CO, CONR⁵⁰, SO₂NR⁵¹,NR⁵²SO₂ or NR⁵³ (wherein R⁴⁹, R⁵⁰, R⁵¹, R⁵² and R⁵³ each independentlyare hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R³⁴ is as definedhereinbefore); 15) C₁₋₃alkylX¹⁰C₁₋₃alkylR³⁴ (wherein X¹⁰ is O, S, SO,SO₂, NR⁵⁴CO, ONR⁵⁵, SO₂NR⁵⁶, NR⁵⁷SO₂ or NR⁵⁸ (wherein R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷and R⁵⁸ each independently are hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R³⁴ is as defined hereinbefore); 16) R³³(wherein R³³ is as defined hereinbefore); and 17)C₁₋₃alkylX¹⁰C₁₋₃alkylR³³ (wherein X¹⁰ and R³³ are as definedhereinbefore); 18) C₁₋₅alkylCOR³³ (wherein R³³ is as definedhereinbefore); n is 0, 1, 2, 3 or 4; and m is 0, 1, 2, 3 or 4; or
 4. 2.The method according to claim 1, wherein R³ is R¹⁰X², wherein X² is O,CH₂, S, SO, SO₂, NR¹¹CO, CONR¹², SO₂NR¹³ NR¹⁴SO₂ or NR¹⁵ (wherein R¹¹,R¹², R¹³, R¹⁴ and R¹⁵ each independently are hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl), or X² is a direct bond; and R¹⁰ is selected fromone of the following groups: 1) hydrogen or C₁₋₅alkyl which may besubstituted with one or more groups selected independently from hydroxy,fluoro and amino; 2) C₁₋₅alkylX³COR¹⁶ (wherein X³ is O or NR¹⁷ (whereinR¹⁷ is hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹⁶ is C₁₋₃alkyl,NR¹⁸R¹⁹ or OR²⁰ (wherein R¹⁸, R¹⁹ and R²⁰ each independently arehydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); 3) C₁₋₅alkylX⁴R²¹ (whereinX⁴ is O, S, SO, SO₂, OCO, NR²²CO, CONR²³, SO₂NR²⁴, NR²⁵SO₂ or NR²⁶(wherein R²², R²³, R²⁴, R²⁵ and R²⁶ each independently are hydrogen,C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²¹ is hydrogen, C₁₋₃alkyl,cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclicgroup with one or two heteroatoms selected independently from O, S andN, which C₁₋₃alkyl group may be substituted with one or two substituentsselected independently from oxo, hydroxy, halogeno and C₁₋₄alkoxy andwhich heterocyclic group may be substituted with one or two substituentsselected independently from oxo, hydroxy, halogeno, C₁₋₄alkyl,C₁₋₄hydroxyalkyl and C₁₋₄alkoxy); 4) C₁₋₅alkylX⁵C₁₋₅alkylX⁶R²⁷ (whereinX⁵ and X⁶ each independently are O, S, SO, SO₂, NR²⁸CO, CONR²⁹, SO₂NR³⁰,NR³¹SO₂ or NR³² (wherein R²⁸, R²⁹, R³⁰, R³¹ and R³² each independentlyare hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²⁷ is hydrogen orC₁₋₃alkyl); 5) C₁₋₅alkylR³³ (wherein R³³ is a 5 or 6 membered saturatedheterocyclic group with one or two heteroatoms selected independentlyfrom O, S and N, which heterocyclic group may be substituted with one ortwo substituents selected independently from oxo, hydroxy, halogeno,C₁₋₄alkyl, C₁₋₄hydroxyalkyl and C₁₋₄alkoxy); 6) C₂₋₅alkenylR³³ (whereinR³³ is as defined hereinbefore); 7) C₂₋₅alkynylR³³ (wherein R³³ is asdefined hereinbefore); 8) R³⁴ (wherein R³⁴ is a pyridone group, a phenylgroup or a 5 or 6 membered aromatic heterocyclic group with 1 to 3heteroatoms selected independently from O, N and S, which pyridone,phenyl or heterocyclic group may carry up to 5 substituents selectedindependently from hydroxy, halogeno, amino, C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy,carboxy, cyano, CONR³⁵R³⁶ and NR³⁷ COR³⁸ (wherein R³⁵, R³, R³⁷ and R³⁸each independently are hydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); 9)C₁₋₅alkylR³⁴ (wherein R³⁴ is as defined hereinbefore); 10)C₂₋₅alkenylR³⁴ (wherein R³⁴ is as defined hereinbefore); 11)C₂₋₅alkynylR³⁴ (wherein R³⁴ is as defined hereinbefore); 12)C₁₋₅alkylX⁷R³⁴ (wherein X⁷ is O, S, SO, SO₂, NR³⁹CO, CONR⁴⁰, SO₂NR⁴¹,NR⁴² SO₂ or NR⁴³ (wherein R³⁹, R⁴⁰, R⁴¹, R⁴² and R⁴³ each independentlyare hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R³⁴ is as definedhereinbefore); 13) C₂₋₅alkenylX⁸R³⁴ (wherein X⁸ is O, S, SO, SO₂,NR⁴⁴CO, CONR⁴⁵, SO₂NR⁴⁶, NR⁴⁷SO₂ or NR⁴⁸ (wherein R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷ andR⁴⁸ each independently are hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)and R³⁴ is as defined hereinbefore); 14) C₂₋₅alkynylX⁹R³⁴ (wherein X⁹ isO, S, SO, SO₂, NR⁴⁹CO, CONR⁵⁰, SO₂NR⁵¹, NR⁵² SO₂ or NR⁵³ (wherein R⁴⁹,R⁵⁰, R⁵¹, R⁵² and R⁵³ each independently are hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R³⁴ is as defined hereinbefore); 15)C₁₋₃alkylX¹⁰C₁₋₃alkylR³⁴ (wherein X¹⁰ is O, S, SO, SO₂, NR⁵⁴CO, ONR⁵⁵,SO₂NR⁵⁶, NR⁵⁷SO₂ or NR⁵⁸ (wherein R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷ and R⁵⁸ eachindependently are hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R³⁴ isas defined hereinbefore); 16) R³³ (wherein R³³ is as definedhereinbefore); and 17) C₁₋₃alkylX¹⁰C₁₋₃alkylR³³ (wherein X¹⁰ and R³³ areas defined hereinbefore).
 3. The method according to claim 1, wherein R¹is hydrogen.
 4. The method according to claim 1, wherein R² is halogeno,cyano, nitro, carboxy, C₁₋₄alkoxycarbonyl, trifluoromethyl, C₁₋₃alkyl,C₁₋₃alkoxy, N—C₁₋₄alkylcarbamoyl, N,N-di(C₁₋₄alkyl)carbamoyl,aminosulphonyl, or a group R⁴X¹, wherein X¹ is CONR⁵R⁶, (wherein R⁵ ishydrogen or C₁₋₂alkyl, and R⁶ is C₁₋₄alkyl, and wherein R⁴ is linked toR⁶); and R⁴ is phenyl or a 5 or 6 membered heterocyclic group with oneor two heteroatoms, selected independently from O and N, whichheterocyclic group may be saturated or unsaturated and which phenyl orheterocyclic group may be substituted with one or two substituentsselected independently from hydroxy, halogeno, C₁₋₃alkyl, C₁₋₃alkoxy,C₁₋₃alkanoyloxy, trifluoromethyl, cyano, amino, nitro andC₁₋₄alkoxycarbonyl; n is 0, 1 or
 2. 5. The method according to claim 1,wherein R³ is R¹⁰X², wherein X² is O; and R¹⁰ is selected from one ofthe following groups: 3) C₁₋₅alkylX⁴R²¹ (wherein X⁴ is O or NR²⁶(wherein R²¹ and R²⁶ each independently are hydrogen, C₁₋₃alkyl,cyclopentyl or cyclohexyl)); 4) C₁₋₅alkylX⁵C₁₋₅alkylX⁶R²⁷ (wherein X⁵and X⁶ are O and R²⁷ is hydrogen or C₁₋₃alkyl); 5) C₁₋₅alkylR³³ (whereinR³³ is a 6 membered saturated heterocyclic group with one or twoheteroatoms, selected independently from O and N, which heterocyclicgroup may be substituted with one or two substituents selectedindependently from oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyland C₁₋₄alkoxy); 9) C₁₋₅alkylR³⁴ (wherein R³⁴ is a 5 membered aromaticheterocyclic group with 1 to 3 heteroatoms selected independently from Oand N, which heterocyclic group may carry up to 5 substituents selectedindependently from halogeno, amino, C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy,carboxy, hydoxy, cyano, CONR³⁵R³⁶ and NR³⁷COR³⁸ (wherein R³⁵, R³⁶, R³⁷and R³⁸ each independently are hydrogen, C₁₋₄alkyl orC₁₋₃alkoxyC₂₋₃alkyl)); and 17) C₁₋₃alkylXlOC₁₋₃alkylR³³ (wherein X¹⁰ isO and R³³ are as defined hereinbefore); m is 0, 1 or
 2. 6. The methodaccording to claim 1, wherein R³ is R¹⁰X², wherein X² is O; and R¹⁰ isselected from one of the following groups: 1) hydrogen or C₁₋₅alkyl; 5)C₁₋₅alkylR³³ (wherein R³³ is a 5 or 6 membered saturated heterocyclicgroup with one or two heteroatoms, selected independently from O, S andN, which heterocyclic group may be substituted with one or twosubstituents selected independently from oxo, hydroxy, halogeno,C₁₋₄alkyl, C₁₋₆carbonyl, C₁₋₄hydroxyalkyl and C₁₋₄alkoxy); 18)C₁₋₅alkylCOR³³ (wherein R³³ is as defined hereinbefore).
 7. The methodaccording to claim 1, wherein R³ is R¹⁰X², wherein X² is O; and R¹⁰ is4) C₁₋₅alkylX⁵C₁₋₅alkylX⁶R²⁷ (wherein X⁵ and X⁶ are O and R²⁷ ishydrogen or C₁₋₃alkyl).
 8. The method according to claim 1, wherein theR² is substituted on position 5 and/or 6 and R³ is substituted onposition 6, 7 and/or
 8. 9-12. (cancelled)
 13. A compound which is4-(6-Fluorooxindol-3-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,4-(5-Cyanooxindol-3-yl)-6-methoxy-7-(2-methoxyethoxy)quinazoline,4-(5-Cyanooxindol-3-yl)-7-(2-methoxyethoxy)quinazoline,4-(5-Cyanooxindol-3-yl)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline,4-(5-Cyanooxindol-3-yl)-7-(3-morpholinopropoxy)quinazoline,4-(5-Carbamoyloxindol-3-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,4-(6-Cyanooxindol-3-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,4-(6-Bromooxindol-3-yl)-7-(3-morpholinopropoxy)quinazoline,2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylicacid (4-phenylbutyl)amide,6-Chloro-3-[7-(3-morpholin-4-yl-propoxy)quinazolin-4-yl]-1,3-dihydro-indol-2-onehydrochloride,3-{7-[2-(2-Methoxyethoxy)ethoxy]quinazolin-4-yl}-1,3-dihydroindol-2-onehydrochloride,6-Fluoro-3-[7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]-1,3-dihydro-indol-2-onedihydrochloride,7-Fluoro-3-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]-1,3-dihydroindol-2-onedihydrochloride,3-[7-(3-Morpholin-4-ylpropoxy)quinazolin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carboxylicacid dimethylamide,3-[7-(3-Morpholin-4-ylpropoxy)quinazolin-4-yl]-6-propyl-1H-indol-2-olhydrochloride,6-Ethyl-3-[7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]-1H-indol-2-olhydrochloride,2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylicacid [2-(1-methylpyrrolidin-2-yl)ethyl]amide,2-Hydroxy-3-[7-(2-morpholin-4-ylethoxy)quinazolin-4-yl]-1H-indole-5-carbonitrildihydrochloride,2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylicacid (tetrahydrofuran-2-ylmethyl)amide,2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylicacid (3-morpholin-4-ylpropyl)amide,2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylicacid [2-(1H-imidazol-4-yl)ethyl]amide,2-Hydroxy-3-{7-[2-(2-methoxyethoxy)ethoxy]quinazolin-4-yl}-1H-indole-5-carbonitrilehydrochloride,3-[7-(2-Imidazol-1-yl-ethoxy)-6-methoxyquinazolin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-sulfonamideacetate,6-Bromo-3-[6-methoxy-7-(3-morpholin-4-yl-propoxy)quinazolin-4-yl]-1,3-dihydroindol-2-onedihydrochloride, 6-Bromo-3-quinazolin-4-yl-1,3-dihydroindol-2-one,6-Bromo-3-{6-methoxy-7-[2-(2-methoxyethoxy)ethoxy]quinazolin-4-yl}-1,3-dihydroindol-2-onehydrochloride,3-{7-[2-(2-Morpholin-4-yl-ethoxy)ethoxy]quinazolin-4-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrilehydrochloride,6-Chloro-3-{7-[2-(2-methoxyethoxy)ethoxy]quinazolin-4-yl}-1,3-dihydroindol-2-onehydrochloride,3-{7-[2-(4-Acetylpiperazin-1-yl)ethoxy]quinazolin-4-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrilehydrochloride,5-Chloro-3-{7-[2-(2-methoxyethoxy)ethoxy]quinazolin-4-yl}-1,3-dihydroindol-2-onehydrochloride,3-{7-[2-(4-Butyrylpiperazin-1-yl)ethoxy]quinazolin-4-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrilehydrochloride,3-{7-[2-(4-Acetylpiperazin-1-yl)-2-oxoethoxy]quinazolin-4-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrilehydrochloride,3-{7-[4-(4-Acetylpiperazin-1-yl)-4-oxobutoxy]quinazolin-4-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrilehydrochloride,6-Bromo-3-[7-(2-imidazol-1-ylethoxy)-6-methoxyquinazolin-4-yl]-1,3-dihydro-indol-2-onedihydrochloride,3-[7-(2-Imidazol-1-ylethoxy)-6-methoxyquinazolin-4-yl]-2-oxo-2,3-dihydro-1H-indole-6-carbonitriledihydrochloride,3-[7-(3-Morpholin-4-ylpropoxy)quinazolin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carboxylicacid methylamide,3-{7-[3-(4-Methylpiperazin-1-yl)propoxy]quinazolin-4-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrilehydrochloride,2-Hydroxy-3-[8-(2-morpholih-4-ylethoxy)quinazolin-4-yl]-1H-indole-5-carbonitrilehydrochloride,6-Bromo-3-[7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carboxylicacid methylamide,6-Methyl-3-[7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]-1H-indol-2-ol,5-Bromo-6-methyl-3-[7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]-1H-indol-2-oldihydrochloride,6-Bromo-3-[7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]-5-nitro-1H-indol-2-oldihydrochloride and or2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylicacid as a free base or salts a salt thereof.
 14. A compound which is3-[7-(3-Dimethylaminopropoxy)quinazolin-4-yl]-2-hydroxy-1H-indol-5-carbonitrilehydrochloride,3-[7-(2-Dimethylaminoethoxy)quinazolin-4-yl]-2-hydroxy-1H-indol-5-carbonitrilefumarate,3-{7-[2-(Isopropylmethylamino)ethoxy]quinazolin-4-yl}-2-oxo-2,3-dihydro-1H-indol-5-carbonitrilefumarate or3-[7-(2-Diisopropylamino)ethoxy)quinazolin-4-yl]-2-hydroxy-1H-indol-5-carbonitrilefumarate, as a free base or a salt thereof. 15-20. (canceled)
 21. Apharmaceutical composition for use in prevention and/or treatment ofdementia related diseases, Alzheimer's Disease and conditions associatedwith glycogen synthase kinase-3, comprising a therapeutically effectiveamount of a compound of formula I as defined in claim 1, andpharmaceutically acceptable carriers or diluents.
 22. A pharmaceuticalcomposition is comprising a therapeutically effective amount of acompound as defined in claim 13 or 14 and pharmaceutically acceptablecarriers or diluents.
 23. (canceled)
 24. A method of prevention and/ortreatment of dementia related diseases, Alzheimer's Disease andconditions associated with glycogen synthase kinase-3 comprisingadministering to a patient in need of such prevention and/or treatment atherapeutically effective amount of a compound defined as in claim 13 or14.
 25. A process for the preparation of a compound of formula Iaccording to claim 1, comprising:

reacting a compound of formula B (IV, VI, VII, XI), wherein L⁴ is aleaving group or SCH₃ with a compound of formula C, to obtain a compoundof formula I, wherein R¹, R², R³, m and n are as defined in claim 1, or,

hydrolysis of a compound of formula Ia, wherein R² is C₁₋₆alkoxycarbonylto obtain a compound of formula Ib, wherein R² is carboxy and R¹, R³, mand n are as defined in claim 1, or,

amidation of a compound of formula Ib, wherein R² is carboxy to obtain acompound of formula Ic, wherein R² is R⁴X¹ and X¹ is CONR⁵R⁶, and R¹,R³, R⁴, R⁵, R⁶, m and n are as defined in claim
 1. 26. A compound whichis 7-(2-Morpholin-4-yl)ethoxy)-3H-quinazolin-4-one,4-Chloro-7-[(2-morpholin-4-yl)ethoxy]quinazoline,7-[2-(2-Methoxyethoxy)ethoxy]-3H-quinazolin-4-one,4-Chloro-7-[2-(2-methoxyethoxy)ethoxy]quinazoline,4-(Methylthio)-7-[2-(2-morpholin-4-ylethoxy)ethoxy]quinazoline,7-[2-(4-Acetylpiperazin-1-yl)ethoxy]-4-methylthioquinazoline,7-(2-Bromoethoxy)-4-(methylthio)quinazoline,7-[2-(4-Butyrylpiperazin-1-yl)ethoxy]-4-(methylthio)quinazoline,7-[2-(4-Acetylpiperazin-1-yl)-2-oxoethoxy]-4-(methylthio)quinazoline,1-Acetyl-4-(4-chlorobutanoyl)piperazine,7-[4-(4-Acetylpiperazin-1-yl)-4-oxobutoxy]-4-(methylthio)quinazoline,2-Oxo-2,3-dihydro-1H-indole-5-carboxylic acid dimethylamide,2-Oxo-2,3-dihydro-1H-indole-5-carboxylic acid methylamide,7-[3-(4-Methylpiperazin-1-yl)propoxy]-3H-quinazolin-4-one,4-Chloro-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline,4-Chloro-8-(2-morpholin-4-ylethoxy)quinazoline,6-Bromo-5-(2-chloroacetyl)1,3-dihydroindol-2-one,6-Bromo-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid,6-Bromo-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methylamide,2-(4-Ethylphenyl)-N-methoxyacetamide,6-Ethyl-1-methoxy-1,3-dihydroindol-2-one,6-Ethyl-1,3-dihydroindol-2-one, N-Methoxy-2-(4-propylphenyl)acetamide,1-Methoxy-6-propyl-1,3-dihydroindol-2-one,6-Propyl-1,3-dihydroindol-2-one, 5-Bromo-6-methyl-1,3-dihydroindol-2-oneand or 6-Bromo-5-nitro-1,3-dihydroindol-2-one, as a free base or a saltthereof.
 27. A compound which is7-(3-Dimethylaminopropoxy)-3H-quinazolin-4-one,7-(2-Dimethylaminoethoxy)-3H-quinazolin-4-one,7-[2-(Isopropylmethylamino)ethoxy]-3H-quinazolin-4-one,7-(2-Diisopropylaminoethoxy)-3H-quinazolin-4-one,[3-(4-Chloroquinazolin-7-yloxy)propyl]dimethylamine,[2-(4-Chloroquinazolin-7-yloxy)ethyl]dimethylamine,[2-(4-Chloroquinazolin-7-yloxy)ethyl]isopropylmethylamine and or[2-(4-Chloro-quinazolin-7-yloxy)ethyl]diisopropylamine, as a free baseor a salt thereof.
 28. (canceled)
 29. The method according to any one ofclaims 1, 13 or 14 wherein the dementia related disease is selected fromthe group of medical conditions consisting of Frontotemporal dementiaParkinson's Type, Parkinson dementia complex of Gaum, HIV dementia,diseases with associated neurofibrillar tangle pathologies, predementedstates, vascular dementia, dementia with Lewy bodies, Frontotemporaldementia, and dementia pugilistica.
 30. A method of prevention and/ortreatment of a medical condition selected from the group consisting ofamyotrophic lateral sclerosis, corticobasal degeneration, Down syndrome,Huntington's Disease, Parkinson's Disease, postencephelaticparkinsonism, progressive supranuclear palsy, Pick's Disease,Niemann-Pick's Disease, stroke, head trauma and other chronicneurodegenerative diseases, Bipolar Disease, affective disorders,depression, schizophrenia, cognitive disorders, hair loss andcontraceptive medication, the method comprising administering to amammal in need of such prevention and/or treatment, a therapeuticallyeffective amount of the compound of formula I as defined in claim
 1. 31.A method of prevention and/or treatment of a medical condition selectedfrom the group consisting of Mild Cognitive Impairment, Age-AssociatedMemory Impairment, Age-Related Cognitive Decline, Cognitive ImpairmentNo Dementia, mild cognitive decline, mild neurocognitive decline,Late-Life Forgetfulness, memory and cognitive impairment andandrogenetic alopecia, the method comprising administering to a mammalin need of such prevention and/or treatment, a therapeutically effectiveamount of the compound of formula I as defined in claim 1.